Combination therapy including a matrix metalloproteinase inhibitor and an antineoplastic agent

ABSTRACT

The present invention provides methods to treat or prevent neoplasia disorders in a mammal using a combination of a matrix metalloproteinase inhibitor and an antineoplastic agent.

This application is a continuation of application Ser. No. 09/857,995filed on Oct. 5, 2001 now U.S. Pat. No. 6,858,598, which is the nationalstage of International Application No. PCT/US99/30699 filed on Dec. 22,1999, which claims priority of U.S. provisional application Ser. No.60/113,786 filed on Dec. 23, 1998.

FIELD OF THE INVENTION

The present invention relates to combinations and methods for treatmentor prevention of neoplasia disorders in a mammal using two or morecomponents with at least one component being a matrix metalloproteinaseinhibitor.

BACKGROUND OF THE INVENTION

A neoplasm, or tumor, is an abnormal, unregulated, and disorganizedproliferation of cell growth. A neoplasm is malignant, or cancerous, ifit has properties of destructive growth, invasiveness and metastasis.Invasiveness refers to the local spread of a neoplasm by infiltration ordestruction of surrounding tissue, typically breaking through the basallaminas that define the boundaries of the tissues, thereby oftenentering the body's circulatory system. Metastasis typically refers tothe dissemination of tumor cells by lymphotics or blood vessels.Metastasis also refers to the migration of tumor cells by directextension through serous cavities, or subarachnoid or other spaces.Through the process of metastasis, tumor cell migration to other areasof the body establishes neoplasms in areas away from the site of initialappearance.

Cancer is now the second leading cause of death in the United States andover 8,000,000 persons in the United States have been diagnosed withcancer. In 1995, cancer accounted for 23.3% of all deaths in the UnitedStates. (See U.S. Dept. of Health and Human Services, National Centerfor Health Statistics, Health United States 1996-97 and Injury Chartbook117 (1997)).

Cancer is not fully understood on the molecular level. It is known thatexposure of a cell to a carcinogen such as certain viruses, certainchemicals, or radiation, leads to DNA alteration that inactivates a“suppressive” gene or activates an “oncogene”. Suppressive genes aregrowth regulatory genes, which upon mutation, can no longer control cellgrowth. Oncogenes are initially normal genes (called prooncogenes) thatby mutation or altered context of expression become transforming genes.The products of transforming genes cause inappropriate cell growth. Morethan twenty different normal cellular genes can become oncogenes bygenetic alteration. Transformed cells differ from normal cells in manyways, including cell morphology, cell-to-cell interactions, membranecontent, cytoskeletal structure, protein secretion, gene expression andmortality (transformed cells can grow indefinitely).

Cancer is now primarily treated with one or a combination of three typesof therapies: surgery, radiation, and chemotherapy. Surgery involves thebulk removal of diseased tissue. While surgery is sometimes effective inremoving tumors located at certain sites, for example, in the breast,colon, and skin, it cannot be used in the treatment of tumors located inother areas, such as the backbone, nor in the treatment of disseminatedneoplastic conditions such as leukemia.

Chemotherapy involves the disruption of cell replication or cellmetabolism. It is used most often in the treatment of breast, lung, andtesticular cancer.

The adverse effects of systemic chemotherapy used in the treatment ofneoplastic disease is most feared by patients undergoing treatment forcancer. Of these adverse effects nausea and vomiting are the most commonand severe side effects. Other adverse side effects include cytopenia,infection, cachexia, mucositis in patients receiving high doses ofchemotherapy with bone marrow rescue or radiation therapy; alopecia(hair loss); cutaneous complications (see M. D. Abeloff, et al: Alopeciaand Cutaneous Complications. P. 755-56. In Abeloff, M. D., Armitage, J.O., Lichter, A. S., and Niederhuber, J. E. (eds) Clinical Oncology.Churchill Livingston, New York, 1992, for cutaneous reactions tochemotherapy agents), such as pruritis, urticaria, and angioedema;neurological complications; pulmonary and cardiac complications inpatients receiving radiation or chemotherapy; and reproductive andendocrine complications.

Chemotherapy-induced side effects significantly impact the quality oflife of the patient and may dramatically influence patient compliancewith treatment.

Additionally, adverse side effects associated with chemotherapeuticagents are generally the major dose-limiting toxicity (DLT) in theadministration of these drugs. For example, mucositis, is one of themajor dose limiting toxicity for several anticancer agents, includingthe antimetabolite cytotoxic agents 5-FU, methotrexate, and antitumorantibiotics, such as doxorubicin. Many of these chemotherapy-inducedside effects if severe, may lead to hospitalization, or requiretreatment with analgesics for the treatment of pain.

The adverse side effects induced by chemotherapeutic agents andradiation therapy have become of major importance to the clinicalmanagement of cancer patients.

The use of TNP-470 and minocycline in combination with cyclophasphamide,CDDP, or thiotepa have been observed to substantially increase the tumorgrowth delay in one pre-clinical solid tumor model. (Teicher, B. A. etal., Breast Cancer Research and Treatment, 36: 227-236, 1995).Additionally, improved results were observed when TNP-470 andminocycline were used in combination with cyclophosphamide andfractionated radiation therapy. (Teicher, B. A. et al., European Journalof Cancer 32A (14): 2461-2466, 1996). Neri et al. examined the use ofAG-3340 in combination with carboplatin and taxol for the treatment ofcancer. (Neri et al., Proc Am Assoc Can Res, Vol 39, 89 meeting, 3021998). U.S. Pat. No. 5,837,696 describes the use of tetracyclinecompounds to inhibit cancer growth. WO 97/48,685 describes varioussubstituted compounds that inhibit metalloproteases. EP 48/9,577describes peptidyl derivatives used to prevent tumor cell metastasis andinvasion. WO 98/25,949 describes the use of N5-substituted5-amino-1,3,4-thiadiazole-2-thiols to inhibit metallopreteinase enzymes.WO 99/21,583 describes a method of inhibiting metastases in patientshaving cancer in which wildtype p53 is predominantly expressed using acombination of radiation therapy and a selective matrixmetalloproteinase-2 inhibitor. WO 98/33,768 describes arylsulfonylaminohydroxamic acid-derivatives in the treatment of cancer. WO 98/30,566describes cyclic sulfone derivatives useful in the treatment of cancer.WO 98/34,981 describes arylsulfonyl hydroxamic acid derivatives usefulin the treatment of cancer. WO 98/33,788 discloses the use of carboxylicor hyroxamic acid derivatives for treatment of tumors. WO 97/41,844describes a method of using combinations of angiostatic compounds forthe prevention and/or treatment of neovascularization in human patients.EP 48/9,579 describes peptidyl derivatives with selective gelatinaseaction that may be of use in the treatment of cancer and to controltumor metastases. WO 98/11,908 describes the use of carboxylic orhyroxamic acid derivatives and a cyclosporin in combination therapy fortreating mammals suffering from arthritic disease. WO 98/03,516describes phasphinate based compounds useful in the treatment of cancer.WO 95/23,811 describes novel carbocyclic compounds which inhibitplatelet aggregation. Wo 93/24,475 describes sulphamide derivatives maybe useful in the treatment of cancer to control the development ofmetastases. WO 98/16,227 describes a method of using[Pyrozol-1-yl]benzenesulfonamides in the treatment of and prevention ofneoplasia. WO 98/22,101 describes a method of using[Pyrozol-1-yl]benzenesulfonamides as anti-angiogenic agents. U.S. Pat.No. 5,854,205 describes an isolated endostatin protein that is aninhibitor of endothelial cell proliferation and angiogenesis. U.S. Pat.No. 5,843,925 describes a method for inhibiting angiogenesis andendothelial cell proliferation using a 7-[substitutedamino]-9-[(substituted glycyloamido]-6-demethyl-6-deoxytetracycline.U.S. Pat. No. 5,863,538 describes methods and compositions for targetingtumor vasculature of solid tumors using immunological and growthfactor-based reagents in combination with chemotherapy and radiation.U.S. Pat. No. 5,837,682 describes the use of fragments of an endothelialcell proliferation inhibitor, angiostatin. U.S. Pat. No. 5,861,372describes the use of an aggregate endothelial inhibitor, angiostatin,and it use in inhibiting angiogenesis. U.S. Pat. No. 5,885,795 describesmethods and compositions for treating diseases mediated by undesired anduncontrolled angiogenesis by administering purified angiostatin orangiostatin derivatives. PCT/GB97/00650 describes the use of cinnolinederivatives for use in the production of an antiangiogenic and/orvascular permeability reducing effect. PCT/US97/09610 describesadministration of an anti-endogin monoclonal antibody, or fragmentsthereof, which is conjugated to at least one angiogenesis inhibitor orantitumor agent for use in treating tumor and angiogenesis-associateddiseases. PCT/IL96/00012 describes a fragment of the Thrombin B-chainfor the treatment of cancer. PCT/US95/16855 describes compositions andmethods of killing selected tumor cells using recombinant viral vectors.Ravaud, A. et al. describes the efficacy and tolerance of interleukin-2(IL-2), interferon alpha-2a, and fluorouracil in patients withmetastatic renal cell carcinoma. J.Clin.Oncol. 16, No. 8, 2728-32, 1998.Stadler, W. M. et al. describes the response rate and toxicity of oral13-cis-retinoic acid added to an outpatient regimen of subcutaneousinterleukin-2 and interferon alpha in patients with metastatic renalcell carcinoma. J.Clin.Oncol. 16, No. 5, 1820-25, 1998 Rosenbeg, S. A.et al. describes treatment of patients with metastatic melanoma usingchemotherapy with cisplatin, dacarbazine, and tamoxifen alone or incombination with interleukin-2 and interferon alpha-2b. J.Clin.Oncol.17, No. 3, 968-75, 1999. Tourani, J-M. et al describes treatment ofrenal cell carcinoma using interleukin-2, and interferon alpha-2aadministered in combination with fluorouracil. J.Clin.Oncol. 16, No. 7,2505-13, 1998. Majewski, S. describes the anticancer action ofretinoids, vitamin D3 and cytokines (interferons and interleukin-12) asrelated to the antiangiogenic and antiproliferative effects.J.Invest.Dermatol. 108, No. 4, 571, 1997. Ryan, C. W. describestreatment of patients with metastatic renal cell cancer with GM-CSF,Interleukin-2, and interferon-alpha plus oral cis-retinoic acid inpatients with metastatic renal cell cancer. J.Invest.Med. 46, No. 7,274A, 1998. Tai-Ping, D. describes potential anti-angiogenic therapies.Trends Pharmacol.Sci. 16, No. 2, 57-66, 1995. Brembeck, F. H. describesthe use of 13-cis retinoic acid and interferon alpha to treat UICC stageIII/IV pancreatic cancer. Gastroenterology 114, No. 4, Pt. 2, A569,1998. Brembeck, F. H. describes the use of 13-cis retinoic acid andinterferon alpha in patients with advanced pancreatic carcinoma. Cancer83, No. 11, 2317-23, 1998. Mackean, M. J. describes the use ofroquinimex (Linomide) and alpha interferon in patients with advancedmalignant melanoma or renal carcinoma. Br.J.Cancer 78, No. 12, 1620-23,1998 Jayson, G. C. describes the use of interleukin 2 andinterleukin-interferon alpha in advanced renal cancer. Br.J.Cancer 78,No. 3, 366-69, 1998. Abraham, J. M. describes the use of Interleukin-2,interferon alpha and 5-fluorouracil in patients with metastatic renalcarcinoma. Br.J.Cancer 78, Suppl. 2, 8, 1998. Soori, G. S. describes theuse of chemo-biotherapy with chlorambucil and alpha interferon inpatients with non-hodgkins lymphoma. Blood 92, No. 10, Pt. 2 Suppl. 1,240b, 1998. Enschede, S. H. describes the use of interferon alpha addedto an anthracycline-based regimen in treating low grade and intermediategrade non-hodgkin's lymphoma. Blood 92, No. 10, Pt. 1 Suppl. 1, 412a,1998. Schachter, J. describes the use of a sequential multi-drugchemotherapy and biotherapy with interferon alpha, a four drugchemotherapy regimen and GM-CSF. Cancer Biother.Radiopharm. 13, No. 3,155-64, 1998. Mross, K. describes the use of retinoic acid, interferonalpha and tamoxifen in metastatic breast cancer patients. J.Cancer Res.Clin. Oncology. 124 Suppl. 1 R123, 1998. Muller, H. describes the use ofsuramin and tamoxifen in the treatment of advanced and metastaticpancreatic carcinoma. Eur.J.Cancer 33, Suppl. 8, S50, 1997. Rodriguez,M. R. describes the use of taxol and cisplatin, and taxotere andvinorelbine in the treatment of metastatic breast cancer. Eur.J.Cancer34, Suppl. 4, S17-S18, 1998. Formenti, C. describes concurrentpaclitaxel and radiation therapy in locally advanced breast cancerpatients. Eur.J.Cancer 34, Suppl. 5, S39, 1998. Durando, A. describescombination chemotherapy with paclitaxel (T) and epirubicin (E) formetastatic breast cancer. Eur.J.Cancer 34, Suppl. 5, S41, 1998. Osaki,A. describes the use of a combination therapy with mitomycin-C,etoposide, doxifluridine and medroxyprogesterone acetate as second-linetherapy for advanced breast cancer. Eur.J.Cancer 34, Suppl. 5, S59,1998.

DESCRIPTION OF THE INVENTION

Treatment or prevention of a neoplasia disorder in a mammal in need ofsuch treatment or prevention is provided by methods and combinationsusing two or more components with at least one component being a matrixmetalloproteinase (MMP) inhibitor.

The method comprises treating said mammal with a therapeuticallyeffective amount of a combination comprising a combination of two ormore agents. The first agent is a matrix metalloproteinase inhibitor(MMP), and the additional component or components is optionally selectedfrom (a) an antiangiogenesis agent; (b) an antineoplastic agent; (c) anadjunctive agent; (d) an immunotherapeutic agent; (e) a device; (f) avaccine; (g) an analgesic agent; and (h) a radiotherapeutic agent;provided that the additional component(s) is other than thecycloxygenase-2 inhibitor selected as the first component and the matrixmetalloproteinase inhibitor selected as the second component.

In one embodiment the combination comprises a matrix metalloproteinaseinhibitor and an antineoplastic agent.

Besides being useful for human treatment, the present invention is alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. More preferredanimals include horses, dogs, and cats.

The methods and combinations of the present invention may be used forthe treatment or prevention of neoplasia disorders including acrallentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycsticcarcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytictumors, bartholin gland carcinoma, basal cell carcinoma, bronchial glandcarcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous,cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma,clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrialhyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma,ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodularhyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma,hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma,hepatic adenomatosis, hepatocellular carcinoma, insulinoma,intaepithelial neoplasia, interepithelial squamous cell neoplasia,invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma,lentigo maligna melanomas, malignant melanoma, malignant mesothelialtumors, medulloblastoma, medulloepithelioma, melanoma, meningeal,mesothelial, metastatic carcinoma, mucoepidermoid carcinoma,neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cellcarcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide,papillary serous adenocarcinoma, pineal cell, pituitary tumors,plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma,retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cellcarcinoma, soft tissue carcinomas, somatostatin-secreting tumor,squamous carcinoma, squamous cell carcinoma, submesothelial, superficialspreading melanoma, undifferentiatied carcinoma, uveal melanoma,verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm'stumor.

The methods and combinations of the present invention provide one ormore benefits. Combinations of MMP inhibitors with the compounds,combinations, agents and therapies of the present invention are usefulin treating and preventing neoplasia disorders. Preferably, the MMPinhibitor or inhibitors and the compounds, combinations, agents andtherapies of the present invention are administered in combination at alow dose, that is, at a dose lower than has been conventionally used inclinical situations.

A benefit of lowering the dose of the compounds, combinations, agentsand therapies of the present invention administered to a mammal includesa decrease in the incidence of adverse effects associated with higherdosages. For example, by the lowering the dosage of a chemotherapeuticagent such as methotrexate, a reduction in the frequency and theseverity of nausea and vomiting will result when compared to thatobserved at higher dosages. Similar benefits are contemplated for thecompounds, compositions, agents and therapies in combination with theMMP inhibitors of the present invention.

By lowering the incidence of adverse effects, an improvement in thequality of life of a patient undergoing treatment for cancer iscontemplated. Further benefits of lowering the incidence of adverseeffects include an improvement in patient compliance, a reduction in thenumber of hospitalizations needed for the treatment of adverse effects,and a reduction in the administration of analgesic agents needed totreat pain associated with the adverse effects.

Alternatively, the methods and combination of the present invention canalso maximize the therapeutic effect at higher doses.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

When used as a therapeutic the compounds described herein are preferablyadministered with a physiologically acceptable carrier. Aphysiologically acceptable carrier is a formulation to which thecompound can be added to dissolve it or otherwise facilitate itsadministration. Examples of physiologically acceptable carriers include,but are not limited to, water, saline, physiologically buffered saline.Additional examples are provided below.

The term “pharmaceutically acceptable” is used adjectivally herein tomean that the modified noun is appropriate for use in a pharmaceuticalproduct. Pharmaceutically acceptable cations include metallic ions andorganic ions. More preferred metallic ions include, but are not limitedto appropriate alkali metal salts, alkaline earth metal salts and otherphysiological acceptable metal ions. Exemplary ions include aluminum,calcium, lithium, magnesium, potassium, sodium and zinc in their usualvalences. Preferred organic ions include protonated tertiary amines andquaternary ammonium cations, including in part, trimethylamine,diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocaine. Exemplary pharmaceutically acceptable acids include withoutlimitation hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaricacid, maleic acid, malic acid, citric acid, isocitric acid, succinicacid, lactic acid, gluconic acid, glucuronic acid, pyruvic acidoxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamicacid, benzoic acid, and the like.

A compound of the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such,as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa.; 1975. Other examples of drug formulations can be found inLiberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable dilutent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, a contemplated aromatic sulfone hydroximateinhibitor compound can be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, gelatin, acacia gum, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thentableted or encapsulated for convenient administration. Such capsules ortablets can contain a controlled-release formulation as can be providedin a dispersion of active compound in hydroxypropylmethyl cellulose. Inthe case of capsules, tablets, and pills, the dosage forms can alsocomprise buffering agents such as sodium citrate, magnesium or calciumcarbonate or bicarbonate. Tablets and pills can additionally be preparedwith enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. A contemplated aromatic sulfone hydroximate inhibitorcompound can be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

The present invention further includes kits comprising a MMP inhibitorand an antineoplastic agent.

The term “treatment” refers to any process, action, application,therapy, or the like, wherein a mammal, including a human being, issubject to medical aid with the object of improving the mammal'scondition, directly or indirectly.

The term “inhibition,” in the context of neoplasia, tumor growth ortumor cell growth, may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention or chemoprevention.

The term “prevention” includes either preventing the onset of clinicallyevident neoplasia altogether or preventing the onset of a preclinicallyevident stage of neoplasia in individuals at risk. Also intended to beencompassed by this definition is the prevention of initiation formalignant cells or to arrest or reverse the progression of premalignantcells to malignant cells. This includes prophylactic treatment of thoseat risk of developing the neoplasia.

The term “angiogenesis” refers to the process by which tumor cellstrigger abnormal blood vessel growth to create their own blood supply,and is a major target of cancer research. Angiogenesis is believed to bethe mechanism via which tumors get needed nutrients to grow andmetastasize to other locations in the body. Antiangiogenic agentsinterfere with these processes and destroy or control tumors.

Angiogenesis is an attractive therapeutic target because it is amulti-step process that occurs in a specific sequence, thus providingseveral possible targets for drug action. Examples of agents thatinterfere with several of these steps include thrombospondin-1,angiostatin, endostatin, interferon alpha and compounds such as matrixmetalloproteinase (MMP) inhibitors that block the actions of enzymesthat clear and create paths for newly forming blood vessels to follow;compounds, such as ανβ3 inhibitors, that interfere with molecules thatblood vessel cells use to bridge between a parent blood vessel and atumor; agents, such as specific COX-2 inhibitors, that prevent thegrowth of cells that form new blood vessels; and protein-based compoundsthat simultaneously interfere with several of these targets.

Antiangiogenic therapy may offer several advantages over conventionalchemotherapy for the treatment of cancer.

Antiangiogenic agents have low toxicity in preclinical trials anddevelopment of drug resistance has not been observed (Folkman, J.,Seminars in Medicine of the Beth Israel Hospital, Boston 333(26):1757-1763, 1995). As angiogenesis is a complex process, made up of manysteps including invasion, proliferation and migration of endothelialcells, it can be anticipated that combination therapies will be mosteffective. Kumar and Armstrong describe anti-angiogenesis therapy usedas an adjunct to chemotherapy, radiation therapy, or surgery. (Kumar, CC, and Armstrong, L., Tumor-induced angiogenesis: a novel target fordrug therapy?, Emerging Drugs (1997), 2, 175-190).

The phrase “therapeutically-effective” is intended to qualify the amountof each agent that will achieve the goal of improvement in neoplasticdisease severity and the frequency of neoplastic disease over treatmentof each agent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

A “therapeutic effect” or “therapeutic effective amount” is intended toqualify the amount of an anticancer agent required to relieve to someextent one or more of the symptoms of a neoplasia disorder, including,but is not limited to: 1) reduction in the number of cancer cells; 2)reduction in tumor size; 3) inhibition (i.e., slowing to some extent,preferably stopping) of cancer cell infiltration into peripheral organs;3) inhibition (i.e., slowing to some extent, preferably stopping) oftumor metastasis; 4) inhibition, to some extent, of tumor growth; 5)relieving or reducing to some extent one or more of the symptomsassociated with the disorder; and/or 6) relieving or reducing the sideeffects associated with the administration of anticancer agents.

The phrase “combination therapy” (or “co-therapy”) embraces theadministration of a metalloproteinase inhibitor, and an antineoplasticagent as part of a specific treatment regimen intended to provide abeneficial effect from the co-action of these therapeutic agents. Thebeneficial effect of the combination includes, but is not limited to,pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents. Administration of these therapeuticagents in combination typically is carried out over a defined timeperiod (usually minutes, hours, days or weeks depending upon thecombination selected). “Combination therapy” generally is not intendedto encompass the administration of two or more of these therapeuticagents as part of separate monotherapy regimens that incidentally andarbitrarily result in the combinations of the present invention.“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, that is, wherein eachtherapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.Substantially simultaneous administration can be accomplished, forexample, by administering to the subject a single capsule having a fixedratio of each therapeutic agent or in multiple, single capsules for eachof the therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent can be effected by anyappropriate route including, but not limited to, oral routes,intravenous routes, intramuscular routes, and direct absorption throughmucous membrane tissues. The therapeutic agents can be administered bythe same route or by different routes. For example, a first therapeuticagent of the combination selected may be administered by intravenousinjection while the other therapeutic agents of the combination may beadministered orally. Alternatively, for example, all therapeutic agentsmay be administered orally or all therapeutic agents may be administeredby intravenous injection. The sequence in which the therapeutic agentsare administered is not narrowly critical. “Combination therapy” alsocan embrace the administration of the therapeutic agents as describedabove in further combination with other biologically active ingredients(such as, but not limited to, a second and different antineoplasticagent) and non-drug therapies (such as, but not limited to, surgery orradiation treatment). Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

The phrases “low dose” or “low dose amount”, in characterizing atherapeutically effective amount of the antiangiogenesis agent and theantineoplastic agent or therapy in the combination therapy, defines aquantity of such agent, or a range of quantity of such agent, that iscapable of improving the neoplastic disease severity while reducing oravoiding one or more antineoplastic-agent-induced side effects, such asmyelosupression, cardiac toxicity, alopecia, nausea or vomiting.

The phrase “adjunctive therapy” encompasses treatment of a subject withagents that reduce or avoid side effects associated with the combinationtherapy of the present invention, including, but not limited to, thoseagents, for example, that reduce the toxic effect of anticancer drugs,e.g., bone resorption inhibitors, cardioprotective agents; prevent orreduce the incidence of nausea and vomiting associated withchemotherapy, radiotherapy or operation; or reduce the incidence ofinfection associated with the administration of myelosuppressiveanticancer drugs.

The phrases “low dose”, or “low dose amount”, in characterizing atherapeutically effective amount of the antiangiogenesis agent and theantineoplastic agent or therapy in the combination therapy, defines aquantity of such agent, or a range of quantity of such agent, that iscapable of improving the neoplastic disease severity while reducing oravoiding one or more antineoplastic-agent-induced side effects, such asmyelosupression, cardiac toxicity, alopecia, nausea or vomiting.

The phrase “adjunctive therapy” includes agents such as those, forexample, that reduce the toxic effect of anticancer drugs, e.g., boneresorption inhibitors, cardioprotective agents; prevent or reduce theincidence of nausea and vomiting associated with chemotherapy,radiotherapy or operation; or reduce the incidence of infectionassociated with the administration of myelosuppressive anticancer drugs.

The phrase an “immunotherapeutic agent” refers to agents used totransfer the immunity of an immune donor, e.g., another person or ananimal, to a host by inoculation. The term embraces the use of serum orgamma gobulin containing performed antibodies produced by anotherindividual or an animal; nonspecific systemic stimulation; adjuvants;active specific immunotherapy; and adoptive immunotherapy. Adoptiveimmunotherapy refers to the treatment of a disease by therapy or agentsthat include host inoculation of sensitized lymphocytes, transferfactor, immune RNA, or antibodies in serum or gamma globulin.

The phrase a “device” refers to any appliance, usually mechanical orelectrical, designed to perform a particular function.

The phrase a “vaccine” includes agents that induce the patient's immunesystem to mount an immune response against the tumor by attacking cellsthat express tumor associated antigens (TAAs).

The phrase “multi-functional proteins” encompass a variety ofpro-angiogenic factors that include basic and acid fibroblast growthfactors (bFGF and aFGF) and vascular permeability factor/vascularendothelial growth factor (VPF/VEGF) (Bikfalvi, A. et al., EndocrineReviews 18: 26-45, 1997). Several endogenous antiangiogenic factors havealso been characterized as multi-functional proteins and includeangiostatin (O'Reilly et al., Cell (Cambridge, Mass.) 79(2): 315-328,1994), endostatin (O'Reilly et al, Cell (Cambridge, Mass.) 88(2):277-285, 1997), interferon .alpha. (Ezekowitz et al, N. Engl. J. Med.,May 28, 326(22) 1456-1463, 1992), thrombospondin (Good et al, Proc NatlAcad Sci USA 87(17): 6624-6628, 1990; Tolsma et al, J Cell Biol 122(2):497-511, 1993), and platelet factor 4 (PF4) (Maione et al, Science247:(4938): 77-79, 1990).

The phrase an “analgesic agent” refers to an agent that relieves painwithout producing anesthesia or loss of consciousness generally byaltering the perception of nociceptive stimuli.

The phrase a “radiotherapeutic agent” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.

The term “pBATT embraces” or “Protein-Based Anti-Tumor Therapies,”refers to protein-based therapeutics for solid tumors. The pBATTsinclude proteins that have demonstrated efficacy against tumors inanimal models or in humans. The protein is then modified to increase itsefficacy and toxicity profile by enhancing its bioavailability andtargeting.

“Angiostatin” is a 38 kD protein comprising the first three or fourkringle domains of plasminogen and was first described in 1994(O'Reilly, M. S. et al., Cell (Cambridge, Mass.) 79(2): 315-328, 1994).Mice bearing primary (Lewis lung carcinoma-low metastatic) tumors didnot respond to angiogenic stimuli such as bFGF in a corneal micropocketassay and the growth of metastatic tumors in these mice was suppresseduntil the primary tumor was excised. The factor responsible for theinhibition of angiogenesis and tumor growth was designated mouseangiostatin. Angiostatin was also shown to inhibit the growth ofendothelial cells in vitro.

Human angiostatin can be prepared by digestion of plasminogen by porcineelastase (O'Reilly, et al., Cell 79(2): 315-328, 1994) or with humanmetalloelastase (Dong et al., Cell 88, 801-810, 1997). The angiostatinproduced via porcine elastase digestion inhibited the growth ofmetastases and primary tumors in mice. O'Reilly et al., (Cell 79(2):315-328, 1994) demonstrated that human angiostatin inhibited metastasisof Lewis lung carcinoma in SCID mice. The same group (O'Reilly, M. S. etal., Nat. Med. (N.Y.) 2(6): 689-692, 1996) subsequently showed thathuman angiostatin inhibited the growth of the human tumors PC3 prostatecarcinoma, clone A colon carcinoma, and MDA-MB breast carcinoma in SCIDmice. Human angiostatin also inhibited the growth of the mouse tumorsLewis lung carcinoma, T241 fibrosarcoma and M5076 reticulum cellcarcinoma in C57B1 mice. Because these enzymatically-preparedangiostatins are not well characterized biochemically, the precisecomposition of the molecules is not known.

Angiostatins of known composition can be prepared by means ofrecombinant DNA technology and expression in heterologous cell systems.Recombinant human angiostatin comprising Kringle domains one throughfour (K1-4) has been produced in the yeast Pichia pastoris (Sim et al.,Cancer Res 57: 1329-1334, 1997). The recombinant human protein inhibitedgrowth of endothelial cells in vitro and inhibited metastasis of Lewislung carcinoma in C57Bl mice. Recombinant murine angiostatin (K1-4) hasbeen produced in insect cells (Wu et al., Biochem Biophys Res Comm 236:651-654, 1997). The recombinant mouse protein inhibited endothelial cellgrowth in vitro and growth of primary Lewis lung carcinoma in vivo.These experiments demonstrated that the first four kringle domains aresufficient for angiostatin activity but did not determine which kringledomains are necessary.

Cao et al. (J. Biol. Chem. 271: 29461-29467, 1996), produced fragmentsof human plasminogen by proteolysis and by expression of recombinantproteins in E. coli. These authors showed that kringle one and to alesser extent kringle four of plasminogen were responsible for theinhibition of endothelial cell growth in vitro. Specifically, kringles1-4 and 1-3 inhibited at similar concentrations, while K1 aloneinhibited endothelial cell growth at four-fold higher concentrations.Kringles two and three inhibited to a lesser extent. More recently Caoet al. (J Biol Chem 272: 22924-22928, 1997), showed that recombinantmouse or human kringle five inhibited endothelial cell growth at lowerconcentrations than angiostatin (K1-4). These experiments demonstratedin vitro angiostatin-like activity but did not address in vivo actionagainst tumors and their metastases.

PCT publication WO 95/29242 discloses purification of a protein fromblood and urine by HPLC that inhibits proliferation of endothelialcells. The protein has a molecular weight between 38 kilodaltons and 45kilodaltons and an amino acid sequence substantially similar to that ofa murine plasminogen fragment beginning at amino acid number 79 of amurine plasminogen molecule. PCT publication WO 96/41194, disclosescompounds and methods for the diagnosis and monitoring ofangiogenesis-dependent diseases. PCT publication WO 96/35774 disclosesthe structure of protein fragments, generally corresponding to kringlestructures occurring within angiostatin. It also discloses aggregateforms of angiostatin, which have endothelial cell inhibiting activity,and provides a means for inhibiting angiogenesis of tumors and fortreating angiogenic-mediated diseases.

“Endostatin” is a 20-kDa (184 amino acid) carboxy fragmerit of collagenXVIII, is an angiogenesis inhibitor produced by a hemangioendothelioma(O'Reilly, M. S. et al., Cell (Cambridge, Mass.) 88(2): 277-285, 1997);and WO 97/15666). Endostatin specifically inhibits endothelialproliferation and inhibits angiogenesis and tumor growth. Primary tumorstreated with non-refolded suspensions of E. coli-derived endostatinregressed to dormant microscopic lesions. Toxicity was not observed andimmunohistochemical studies revealed a blockage of angiogenesisaccompanied by high proliferation balanced by apoptosis in tumor cells.

“Interferon .alpha.” (IFN.alpha.) is a family of highly homologous,species-specific proteins that possess complex antiviral, antineoplasticand immunomodulating activities (Extensively reviewed in the monograph“Antineoplastic agents, interferon alfa”, American Society of HospitalPharmacists, Inc., 1996). Interferon .alpha. also hasanti-proliferative, and antiangiogenic properties, and has specificeffects on cellular differentiation (Sreevalsan, in “Biologic Therapy ofCancer”, pp. 347-364, (eds. V. T. DeVita Jr., S. Hellman, and S. A.Rosenberg), J.B. Lippincott Co, Philadelphia, Pa., 1995).

Interferon .alpha. is effective against a variety of cancers includinghairy cell leukemia, chronic myelogenous leukemia, malignant melanoma,and Kaposi's sarcoma. The precise mechanism by which IFN.alpha. exertsits anti-tumor activity is not entirely clear, and may differ based onthe tumor type or stage of disease. The anti-proliferative properties ofIFN.alpha., which may result from the modulation of the expression ofoncogenes and/or proto-oncogenes, have been demonstrated on both tumorcell lines and human tumors growing in nude mice (Gutterman, J. U.,Proc. Natl. Acad. Sci., USA 91: 1198-1205, 1994).

Interferon is also considered an anti-angiogenic factor, as demonstratedthrough the successful treatment of hernangiomas in infants (Ezekowitzet al, N. Engl. J. Med., May 28, 326(22) 1456-1463, 1992) and theeffectiveness of IFN.alpha. against Kaposi's sarcoma (Krown, Semin Oncol14(2 Suppl 3): 27-33, 1987). The mechanism underlying theseanti-angiogenic effects is not clear, and may be the result ofIFN.alpha. action on the tumor (decreasing the secretion ofpro-angiogenic factors) or on the neo-vasculature. IFN receptors havebeen identified on a variety of cell types (Navarro et al., ModernPathology 9(2): 150-156, 1996).

U.S. Pat. No. 4,530,901, by Weissmann, describes the cloning andexpression of IFN-.alpha.-type molecules in transformed host strains.U.S. Pat. No. 4,503,035, Pestka, describes an improved processes forpurifying 10 species of human leukocyte interferon using preparativehigh performance liquid chromatography. U.S. Pat. No. 5,231,176,Goeddel, describes the cloning of a novel distinct family of humanleukocyte interferons containing in their mature form greater than 166and no more than 172 amino acids.

U.S. Pat. No. 5,541,293, by Stabinsky, describes the synthesis, cloning,and expression of consensus human interferons. These are non-naturallyoccurring analogues of human (leukocyte) interferon-.alpha. assembledfrom synthetic oligonucleotides. The sequence of the consensusinterferon was determined by comparing the sequences of 13 members ofthe IFN-.alpha. family of interferons and selecting the preferred aminoacid at each position. These variants differ from naturally occurringforms in terms of the identity and/or location of one or more aminoacids, and one or more biological and pharmacological properties (e.g.,antibody reactivity, potency, or duration effect) but retain other suchproperties.

“Thrombospondin-1” (TSP-1) is a trimer containing three copies of a 180kDa polypeptide. TSP-1 is produced by many cell types includingplatelets, fibroblasts, and endothelial cells (see Frazier, Curr OpinCell Biol 3(5): 792-799, 1991) and the cDNA encoding the subunit hasbeen cloned (Hennessy, et al., 1989, J Cell Biol 108(2): 729-736; Lawlerand Hynes, J Cell Biol 103(5): 1635-1648, 1986). Native TSP-1 has beenshown to block endothelial cell migration in vitro andneovascularization in vivo (Good et al, Proc Natl Acad Sci USA 87(17):6624-6628, 1990). Expression of TSP-1 in tumor cells also suppressestumorigenesis and tumor-induced angiogenesis (Sheibani and Frazier, ProcNatl Acad Sci USA 92(15) 6788-6792, 1995; Weinstat-Saslow et al., CancerRes 54(24):6504-6511, 1994). The antiangiogenic activity of TSP-1 hasbeen shown to reside in two distinct domains of this protein (Tolsma etal, J Cell Biol 122(2): 497-511, 1993). One of these domains consists ofresidues 303 to 309 of native TSP-1 and the other consists of residues481 to 499 of TSP-1. Another important domain consists of the sequenceCSVTCG which appears to mediate the binding of TSP-1 to some tumor celltypes (Tuszynski and Nicosia, Bioessays 18(1): 71-76, 1996).

The phrase “integrin antagonist” includes agents that impair endothelialcell adhesion via the various integrins. Integrin antagonists induceimproperly proliferating endothelial cells to die, by interfering withmolecules that blood vessel cells use to bridge between a parent bloodvessel and a tumor.

Adhesion forces are critical for many normal physiological functions.Disruptions in these forces, through alterations in cell adhesionfactors, are implicated in a variety of disorders, including cancer,stroke, osteoporosis, restenosis, and rheumatoid arthritis (A. F.Horwitz, Scientific American, 276:(5): 68-75, 1997).

Integrins are a large family of cell surface glycoproteins which mediatecell adhesion and play central roles in many adhesion phenomena.Integrins are heterodimers composed of noncovalently linked alpha andbeta polypeptide subunits. Currently eleven different alpha subunitshave been identified and six different beta subunits have beenidentified. The various alpha subunits can combine with various betasubunits to form distinct integrins.

One integrin known as a_(v)b₃ (or the vitronectin receptor) is normallyassociated with endothelial cells and smooth muscle cells. a_(v)b₃integrins can promote the formation of blood vessels (angiogenesis) intumors. These vessels nourish the tumors and provide access routes intothe bloodstream for metastatic cells.

The a_(v)b₃ integrin is also known to play a role in various otherdisease states or conditions including tumor metastasis, solid tumorgrowth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemiaof malignancy, angiogenesis, including tumor angiogenesis, retinopathy,arthritis, including rheumatoid arthritis, periodontal disease,psoriasis, and smooth muscle cell migration (e.g. restenosis).

Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

The a_(v)b₃ integrin and a variety of other a_(v)-containing integrinsbind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules.Compounds containing the RGD sequence mimic extracellular matrix ligandsand bind to cell surface receptors. Fibronectin and vitronectin areamong the major binding partners of a_(v)b₃ integrin. Other proteins andpeptides also bind the a_(v)b₃ ligand. These include the disintegrins(M. Pfaff et al., Cell Adhes. Commun. 2(6): 491-501, 1994), peptidesderived from phage display libraries (Healy, J. M. et al., Protein Pept.Lett. 3(1): 23-30, 1996; Hart, S. L. et al., J. Biol. Chem. 269(17):12468-12474, 1994) and small cyclic RGD peptides (M. Pfaff et al., J.Biol. Chem., 269(32): 20233-20238, 1994). The monoclonal antibody LM609is also an a_(v)b₃ integrin antagonist (D. A. Cheresh et al., J. Biol.Chem., 262(36): 17703-17711, 1987).

A_(v)b₃ inhibitors are being developed as potential anti-cancer agents.Compounds that impair endothelial cell adhesion via the a_(v)b₃ integrininduce improperly proliferating endothelial cells to die.

The a_(v)b₃ integrin has been shown to play a role in melanoma cellinvasion (Seftor et al., Proc. Natl. Acad. Sci. USA, 89: 1557-1561,1992). The a_(v)b₃ integrin expressed on human melanoma cells has alsobeen shown to promote a survival signal, protecting the cells fromapoptosis (Montgomery et al., Proc. Natl. Acad. Sci. USA, 91: 8856-8860,1994).

Mediation of the tumor cell metastatic pathway by interference with thea_(v)b₃ integrin cell adhesion receptor to impede tumor metastasis wouldbe beneficial. Antagonists of a_(v)b₃ have been shown to provide atherapeutic approach for the treatment of neoplasia (inhibition of solidtumor growth) because systemic administration of a_(v)b₃ antagonistscauses dramatic regression of various histologically distinct humantumors (Brooks et al., Cell, 79: 1157-1164, 1994).

The adhesion receptor identified as integrin a_(v)b₃ is a marker ofangiogenic blood vessels in chick and man. This receptor plays acritical role in angiogenesis or neovascularization. Angiogenesis ischaracterized by the invasion, migration and proliferation of smoothmuscle and endothelial cells by new blood vessels. Antagonists ofa_(v)b₃ inhibit this process by selectively promoting apoptosis of cellsin the neovasculature. The growth of new blood vessels, also contributesto pathological conditions such as diabetic retinopathy (Adonis et al.,Amer. J. Ophthal., 118. 445-450, 1994) and rheumatoid arthritis (Peacocket al., J. Exp. Med., 175: 1135-1138, 1992). Therefore, a_(v)b₃antagonists can be useful therapeutic targets for treating suchconditions associated with neovascularization (Brooks et al., Science,264: 569-571, 1994).

The a_(v)b₃ cell surface receptor is also the major integrin onosteoclasts responsible for the attachment to the matrix of bone.Osteoclasts cause bone resorption and when such bone resorbing activityexceeds bone forming activity, osteoporosis (a loss of bone) results,which leads to an increased number of bone fractures, incapacitation andincreased mortality. Antagonists of a_(v)b₃ have been shown to be potentinhibitors of osteoclastic activity both in vitro (Sato et al., J. Cell.Biol., 111: 1713-1723, 1990) and in vivo (Fisher et al., Endocrinology,132: 1411-1413, 1993). Antagonism of a_(v)b₃ leads to decreased boneresorption and therefore assists in restoring a normal balance of boneforming and resorbing activity. Thus it would be beneficial to provideantagonists of osteoclast a_(v)b₃ which are effective inhibitors of boneresorption and therefore are useful in the treatment or prevention ofosteoporosis.

PCT Int. Appl. Wo 97/08145 by Sikorski et al., discloses meta-guanidine,urea, thiourea or azacyclic amino benzoic acid derivatives as highlyspecific a_(v)b₃ integrin antagonists. PCT Int. Appl. WO 96/00574 A1960111 by Cousins, R. D. et. al., describe preparation of3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine and -2-benzazepinederivatives and analogs as vitronectin receptor antagonists. PCT Int.Appl. WO 97/23480 A1 970703 by Jadhav, P. K. et. al. describe annelatedpyrazoles as novel integrin receptor antagonists. Novel heterocyclesincluding3-[1-[3-(imidazolin-2-ylamino)propyl]indazol-5-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid, which are useful as antagonists of thea_(v)b₃ integrin and related cell surface adhesive protein receptors. PTInt. Appl. WO 97/26250 A1 970724 by Hartman, G. D. et al., describe thepreparation of arginine dipeptide mimics as integrin receptorantagonists. Selected compounds were shown to bind to human integrina_(v)b₃ with EIB <1000 nM and claimed as compounds, useful forinhibiting the binding of fibrinogen to blood platelets and forinhibiting the aggregation of blood platelets. PCT Int. Appl. WO97/23451 by Diefenbach, B. et. al. describe a series oftyrosine-derivatives used as alpha v-integrin inhibitors for treatingtumors, osteoporosis, osteolytic disorder and for suppressingangiogenesis. PCT Int. Appl. WO 96/16983 A1 960606, by Vuori, K. andRuoslahti, E. describe cooperative combinations of a_(v)b₃ integrinligand and second ligand contained within a matrix, and use in woundhealing and tissue regeneration. The compounds contain a ligand for thea_(v)b₃ integrin and a ligand for the insulin receptor, the PDGFreceptor, the IL-4 receptor, or the IGF receptor, combined in abiodegradable polymeric (e.g. hyaluronic acid) matrix. PCT Int. Appl. WO97/10507 A1 970320 by Ruoslahti, E; and Pasqualini, R. describe peptidesthat home to a selected organ or tissue in vivo, and methods ofidentifying them. A brain-homing peptide, nine amino acid residues long,for example, directs red blood cells to the brain. Also described is useof in vivo panning to identify peptides homing to a breast tumor or amelanoma. PCT Int. Appl. Wo 96/01653 A1 960125 by Thorpe, Philip E.;Edgington, Thomas S. describes bifunctional ligands for specific tumorinhibition by blood coagulation in tumor vasculature. The disclosedbispecific binding ligands bind through a first binding region to adisease-related target cell, e.g. a tumor cell or tumor vasculature; thesecond region has coagulation-promoting activity or is a binding regionfor a coagulation factor. The disclosed bispecific binding ligand may bea bispecific (monoclonal) antibody, or the two ligands may be connectedby a (selectively cleavable) covalent bond, a chemical linking agent, anavidin-biotin linkage, and the like. The target of the first bindingregion can be a cytokine-inducible component, and the cytokine can bereleased in response to a leukocyte-activating antibody; this may be abispecific antibody which crosslinks activated leukocytes with tumorcells.

The phrase “cyclooxygenase-2 inhibitor” or “COX-2 inhibitor” or“cyclooxygenase-II inhibitor” includes agents that specifically inhibita class of enzymes, cyclooxygenase-2, without significant inhibition ofcyclooxygenase-1. Preferably, it includes compounds which have acyclooxygenase-2 IC₅₀ of less than about 0.2 μM, and also have aselectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1inhibition of at least 50, and more preferably of at least 100. Evenmore preferably, the compounds have a cyclooxygenase-1 IC₅₀ of greaterthan about 1 μM, and more preferably of greater than 10 μM.

Studies indicate that prostaglandins synthesized by cyclooxygenases playa critical role in the initiation and promotion of cancer. Moreover,COX-2 is overexpressed in neoplastic lesions of the colon, breast, lung,prostate, esophagus, pancreas, intestine, cervix, ovaries, urinarybladder, and head & neck. In several in vitro and animal models, COX-2inhibitors have inhibited tumor growth and metastasis. Non-limitingexamples of COX-2 inhibitors include rofecoxib and JTE-522.

The phrase “matrix metalloproteinase inhibitor” or “MMP inhibitor”includes agents that specifically inhibit a class of enzymes, the zincmetalloproteinases (metalloproteases). The zinc metalloproteinases areinvolved in the degradation of connective tissue or connective tissuecomponents. These enzymes are released from resident tissue cells and/orinvading inflammatory or tumor cells. Blocking the action of zincmetalloproteinases interferes with the creation of paths for newlyforming blood vessels to follow. Examples of MMP inhibitors aredescribed in Golub, L M, Inhibition of Matrix Metalloproteinases:Therapeutic Applications (Annals of the New York Academy of Science, Vol878). Robert A. Greenwald and Stanley Zucker (Eds.), June 1999), and ishereby incorporated by reference.

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals makeup, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason leads to a number of disease states. Inhibition ofthe enzymes responsible loss of equilibrium provides a control mechanismfor this tissue decomposition and, therefore, a treatment for thesediseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes reIeased from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; corneal, epidermal orgastric ulceration; tumor metastasis, invasion or angiogenesis;periodontal disease; proteinuria; Alzheimer's Disease; coronarythrombosis and bone disease. Defective injury repair processes alsooccur. This can produce improper wound healing leading to weak repairs,adhesions and scarring. These latter defects can lead to disfigurementand/or permanent disabilities as with post-surgical adhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumornecrosis factor (TNF) and inhibition of the production or action of TNFand related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large integer ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

TNF-α convertase is a metalloproteinase involved in the formation ofactive TNF-α. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in, for example PCT Publication WO 94/24140. Other compoundsthat inhibit both MMPs activity have also been disclosed in WO 94/02466.Still other compounds that inhibit both MMPs activity have beendisclosed in WO 97/20824.

There remains a need for effective MMP and TNF-α convertase inhibitingagents. Compounds that inhibit MMPs such as collagenase, stromelysin andgelatinase have been shown to inhibit the release of TNF (Gearing et al.Nature 376, 555-557 (1994)). McGeehan et al., Nature 376, 558-561 (1994)also reports such findings.

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin (MMP-3), gelatinase(MMP-2), or collagenase III (MMP-13) are the relatively most importantenzyme or enzymes to inhibit especially when compared with collagenase I(MMP-1). A drug that does not inhibit collagenase I can have a superiortherapeutic profile.

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitor of metalloproteinase (TIMP),α₂-macroglobulin and their analogs or derivatives. These are highmolecular weight protein molecules that form inactive complexes withmetalloproteases. An integer of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO 95/12389.Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are also shown in WO 96/11209. Still furhter Thiolgroup-containing amide or peptidyl amide-based metalloprotease (MMP)inhibitors are shown in U.S. Pat. No. 4,595,700. Hydroxamategroup-containing MMP inhibitors are disclosed in a number of publishedpatent applications that disclose carbon back-boned compounds, such asin WO 95/29892. Other published patents include Wo 97/24117.Additionally, EP 0 780 386 further discloses hydroxamategroup-containing MMP inhibitors. WO 90/05719 disclose hydroxamates thathave a peptidyl back-bones or peptidomimetic back-bones. WO 93/20047also discloses hydroxamates that have a peptidyl back-bones orpeptidomimetic back-bones. Additionally, WO 95/09841 discloses disclosehydroxamates that have peptidyl back-bones or peptidomimetic back-bones.And WO 96/06074 further discloses hydroxamates that have peptidylback-bones or peptidomimetic back-bones. Schwartz et al., Progr. Med.Chem., 29:271-334(1992) also discloses disclose hydroxamates that havepeptidyl back-bones or peptidomimetic back-bones. Furthermore, Rasmussenet al., Pharmacol. Ther., 75(1): 69-75 (1997) discloses hydroxamatesthat have peptidyl back-bones or peptidomimetic back-bones. Also, Deniset al., Invest. New Drugs, 15(3): 175-185 (1997) discloses hydroxamatesthat have a peptidyl back-bones or peptidomimetic back-bones as well.

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther.,75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate), indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. The most common drug-relatedtoxicity of marimastat in those clinical trials was musculoskeletal painand stiffness, often commencing in the small joints in the hands,spreading to the arms and shoulder. A short dosing holiday of 1-3 weeksfollowed by dosage reduction permits treatment to continue. Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lackof specificity of inhibitory effect among the MMPs may be the cause ofthat effect.

In view of the importance of hydroxamate MMP inhibitor compounds in thetreatment of several diseases and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be beneficial to use hydroxamates of greater enzyme specificity.This would be particularly the case if the hydroxamate inhibitorsexhibited limited inhibition of MMP-1 that is relatively ubiquitous andas yet not associated with any pathological condition, while exhibitingquite high inhibitory activity against one or more of MMP-2, MMP-9 orMMP-13 that are associated with several pathological conditions.

Non-limiting examples of matrix metalloproteinase inhibitors that may beused in the present invention are identified in Table No. 1, below.

TABLE No. 1 Matrix metalloproteinase inhibitors. Compound Trade NameReference Dosage Biphenyl WO 97/18188 hydroxamate AG-3067 Winter Conf.(Agouron Med. Bio- Pharm. organic Inc.) Chem. 1997 January, 26-31AG-3340 WO 97/20824 50 mg/kg (Agouron treatment Pharm. of Lewis Inc.)lung carcinomas in test animals AG-2024 (Agouron Pharm. Inc.) AG-3365(Agouron Pharm. Inc.) 3(S)-N-hydroxy- WO 97/20824. In female 4-(4-[4-FEBS (1992) Lewis rats, (imidazol-1- 296 (3):263 arthritis yl)phenoxy]model: dose benzenesulfonyl)- of 25 2,2-dimethyl- mg/kg/daytetrahydro-2H- gave 97.5% 1,4-thiazine-3- weight loss carboxamide, andinhibition derivatives thereof Heteroaryl WO 98/17643 succinamidesderivatives AG-3296 (Agouron Pharm. Inc.) AG-3287 (Agouron Pharm. Inc.)AG-3293 (Agouron Pharm. Inc.) AG-3294 (Agouron Pharm. Inc.) AG-3067Winter Conf (Agouron Med Bio- Pharm. organic Chem Inc.) 1997 January26-31 2R,4S)-4- EP 0818443 hydroxy-2- isobutyl-5- mercapto-N- [(1S)-2,2-dimethyl-1- methylcarbamoyl- propyl] pentanamide N-alkyl, N- WO 98/16520phenylsulfonyl- N′-hydroxamic acid derivatives of heteroaryl carboxylicacids Novel N-alkyl, WO 98/16514 phenylsulfonyl - N′-hydroxamic acidderivatives of heteroaryl carboxylic acids Novel N-alkyl, WO 98/16506phenylsulfonyl- N′-hydroxamic acid derivatives of cycloalkane carboxylicacids Novel N-alkyl, WO 98/16503 N- phenylsulfonyl- N′-hydroxamic acidderivatives of anthranilic acid sulfonamido- EP 03/98753 hydroxamic acidderivatives TIMP-3: WO 95/09918 polynucleotides encoding endogenous(human) peptides (3alpha, WO 93/23075 5beta, 6alpha, 7alphabeta)-4′,4′-(hexahydro-2,2- dimethyl-1,3- benzodioxole-5, 6-diyl)bis(2,6-piperazinedione) and derivatives thereof BE-16627B WO 91/08222. Int. J.Cancer 1994 58 5 730- 735 (2S)-4-(4-(4- WO 96/15096 chlorophenyl)phenyl)-4-oxo-2- (2- phthalimidoethyl) butanoic acid Bay-12- WO 96/1509610 to 400 9566 mg/day 4-oxo-2-(2- WO 97/43238 phthalimidoethyl alkanoicacid derivatives Novel 4-(4- WO 97/43237 Alkynylphenyl) 4-oxobutanoicacid derivatives Substituted 4- WO 96/15096 biarylbutyric orbiarylpentanoic acids and derivatives Substituted 4- WO 98/22436biphenyl-4- hydroxybutyric acid derivatives 2R,S)-HONH-CO- J Med ChemCH(i-Bu)-CO-Ala- 1998 41 3 Gly-NH2, 339-345 batimastat; BB- WO 90/0571915 to 135 94; Hydroxamic mg/m2 acid based administer- collagenase edintra- inhibitors pleurally Hydroxamic acid WO 90/05719 basedcollagenase inhibitors marimastat BB- WO 94/02447 5 to 800 mg 2516;Hydroxamic daily acid derivatives alpha-cycloalkyl Bio-organic analogsof Med Chem marimastat Lett 1998 8 11 1359- 1364 GI-245402 (BB-2983)Hydroxamic acid WO 94/21625 derivatives Succinyl WO 95/32944 hydroxamicacid, N-formyl-N- hydroxy amino carboxylic acid and succinic acid amidederivatives hydroxamic acid, WO 97/19053 N-formyl-N- hydroxyamino andcarboxylic acid derivatives, pseudopeptide WO 97/19050 hydroxamic andcarboxylic acid derivatives from the corresponding lactone andalpha-amino acid Succinic acid WO 97/03966. amide GB 95/00111.derivatives GB 95/00121. Hydroxamic acid WO 97/02239 derivativesSuccinamidyl WO 96/33165 (alpha substituted) hydroxamic acid derivatives(2S,3R)-3-[2,2- WO 96/25156 dimethyl-1S- (thiazol-2- ylcarbamoyl)propylcarbamoyl[- 5-methyl-2-(prop- 2-enyl)hexano- hydroxanic acid andderivatives thereof Hydroxamic or WO 96/16931 carboxylic acidderivatives hydroxamic and WO 96/06074 carboxylic acids 2-[(1S)-1-((1R)-WO 98/23588 2-[[1,1′- biphenyl]-4- ylmethylthio]-1- [(1S)-2,2-dimethyl-1- (methylcarbamoyl) propylcarbamoyl] ethylcarbamoyl)-4-(1,3-dioxo- 1,3- dihydroisoindol- 2-yl)butylthio]- acetate, andderivatives thereof Hydroxamic acid WO 95/09841 derivatives asinhibitors of cytokine production Hydroxamic acid WO 94/24140derivatives Aromatic or WO 95/19956 heteroaryl substituted hydroxamic orcarboxylic acid derivatives Hydroxamic acid WO 95/19957 Doses arederivatives preferably 1 to 100 mg/kg. Hydroxamic acid WO 95/19961 Dosesare and carboxylic preferably acid derivatives 1 to 100 mg/kg.Butanediamide, BB-1433 At 50 mg/kg N1- bid. p.o. [1(cyclohexyl-inhibited methyl)-2 bone (methylamino)-2- mineral oxoethyl]-N4,3-density dihydroxy-2-(2- loss methylpropyl)-, [2R[N1(S*),2R*, 3S*]]-tetracycline EP 733369 D-penicill- analogs and D- amine penicillaminereduced allergic encephalitis symptom scores in a dose dependent mannerat 27, 125 and 375 mug with complete inhibition CDP-845 BiochemPharmacol 1990 39 12 2041-2049 succinamide WO 95/04033 oral derivativesbioavail- ability by murine pleural cavity assay in the presence ofgelatinase: Between 73% and 100% inhibition was displayed at 10 mg/kgfor six of the compounds. The seventh displayed 100% inhibition at 80mg/kg. Peptidyl WO 94/25435. derivatives WO 94/25434 Mercaptoalkyl- WO97/19075 peptidyl compounds having an imidazole substituentmercaptoalkyl- WO 97/38007. peptide WO 95/12389. derivatives WO96/11209. Mercaptoalkyl- WO 97/37974 amide derivatives arylsulfonyl- WO97/37973. hydrazine WO 95/12389 derivatives N-acetylthio- WO 96/35714lacetyl-N-(3- phthalimidopropyl) -L-leucyl-L- phenylalanine N-methylamide 2-acetylsulfanyl- WO 96/35712 dosages of 5-phthalimido-about 0.5 pentanoyl-L- mg to 3.5 g leucineN-(2- per day forphenylethyl)- the amide treatment of inflam- mation 5-phthalimido- WO96/35711 pentanoyl-L- leucyl-L- phenylalanineN- methylamide peptidyl WO98/06696 derivatives 4-[4- WO 98/05635 (methoxycarbonyl methoxy)-3,5-dimethylphenyl]- 2-methyl-1(2H)- phthalazinone, and hydroxamic andcarboxylic acid derivatives thio-substituted WO 97/12902 peptidesMercaptoamides WO 97/12861 Peptidyl WO 96/35687 derivatives having SH oracylo groups which are amides, primary amides or thioamides D-5410(Chiro- science Group plc) WO 95/13289 CH-104, (Chiro- science Groupplc) D-2163 (Chiro Science Ltd.) D-1927 (Chiro Science Ltd.) Dermastat(Colla- Genex Pharma- ceutical Inc.) Metastat (Colla- Genex) Osteostat(Colla- Genex Pharma- ceutical Inc.) doxy- Gingival cycline; crevicularRoche; fluid Periostat collagenase is reported to be inhibited atconcentra- tions of 5-10 microg/ml or 15-30 microM 2S, 5R, 6S-3- WO97/18207 aza-4-oxo-10- oxa-5-isobutyl- 2-(N- methylcarbox- amido)-[10]paracyclo- phane-6-N- hydroxycarbox- amide hydroxamic acid WO96/33176 and amino- carboxylate compounds N-hydroxamic WO 96/33166derivatives of succinamide Macrocyclic J Med Chem amino 1998 41 11carboxylates 1749-1751 SE-205 Bio-organic (DuPont Med Chem Merck Lett1998 8 Pharm Co.) 7 837-842. J Med Chem 1998 41 11 1745-1748 macrocyclicmatrix metalloprotease- 8 inhibitors Hydroxamic acid WO 95/22966 andcarboxylic acid derivatives succinamid U.S. Pat. No. derivatives 5256657mercaptosulfide WO 95/09833 derivatives sulfoximine and WO 95/09620sulfodiimine derivatised peptides water soluble WO 96/33968 MMPinhibitors hydantoin EP 06/40594 derivatives Piperazine WO 98/27069derivatives GI-155704A J Med Chem 1994 37 5 674. Bioorganic Med ChemLett 1996 6 16 1905- 1910 Cyclic imide EP 05/20573 derivatives.3-(mercapto- WO 97/48685 methyl) hexa- hydro-2,5- pyrazinedionederivatives beta- WO 96/40738 mercaptoketone and beta- mercaptoalcoholderivatives ilomastat U.S. Pat. No. eye drops MPI; GM- 5114953.containing 6001; Cancer Res ilomastat Galardin 1994 54 17 (800 4715-4718microg/ml Cyclic and WO 97/18194 heterocyclic N- substituted alpha-iminohydroxamic and carboxylic acids Aminomethyl- EP 703239 phosphonicand aminomethyl- phosphinic acids derivatives 3-Mercapto- WO 98/12211acetylamino-1,5- substituted-2- oxo-azepan derivatives 2-substituted WO94/04531 indane-2- mercaptoacetyl- amide tricyclic derivatives Ro-2756(Roche Holding AG) Ro-26-4325 (Roche Holding AG) Ro-26-5726 (RocheHolding AG) Ro-26-6307 (Roche Holding AG) Ro-31-9790 J Am Soc mono-(Roche Nephrol 1995 arthritis Holding 6 3 904. in rat: 100 AG) InflammRes mg/kg/day 1995 44 8 345-349 substituted and WO 92/09556unsubstituted hydroxamates (specifically N- [D,L-2-isobutyl-3-(N′-hydroxy- carbonyl-amido)- propanoyl]trypto- phanmethylamide)GM6001, N-(2(R)- WO 95/24921 2- (hydroxyamino- carbonylmethyl)-4-methylpentanoyl) -L-tryptophan methylamide. Oligonucleotice (c-jun)Sulfated WO 98/11141 polysaccharides KB-R7785; Life Sci KB-R8301; 199761 8 KB-R8845 795-803 Fas ligand WO 97/09066 solubilization inhibitorgelastatin AB, KRIBB KT5-12 Faseb J 1998 (Kotobuki 12 5 A773 Seiyaku Co(4482) Ltd.) 2-(N2-[(2R)-2- GB 23/18789 (2-hydroxyamino- 2-oxoethyl)-5-(4- methoxyphenoxy)p pentanoyl]-L- phenylalanylamino) ethanesulfonamide,and carboxylic acid derivatives thereof Chromone EP 758649 2-derivatives Pyrolylthio- chromone in a murine melanoma model produced37% inhibition at 100 mg/kg Esculetin EP 719770 derivatives, substitutedand WO 92/09563 unsubstituted hyroxyureas and reverse hydroxamatesSynthetic MMP WO 94/22309 inhibitors (ex. N-(D,L-2- isobutyl-3-(N′-hydroxycarbonyl- amido)propanoyl) tryptophan methylamide) Reverse WO95/19965 in female hydroxamates and mice hydroxyureas infected w/murinemelanoma - init 80 mug followed by 150 mg/kg/day N- U.S. Pat. No.(mercaptoacyl)- 5629343 aryl derivatives of leucine and phenylalanineN-carboxyalkyl WO 95/29689 derivatives Substituted GB 22/82598Inflammation cyclic is stated derivatives to be effectively treated byoral administration of 0.01 to 50 mg/kg Substituted n- GB 22/72441carboxyalkyldi- peptides (2S,4R)-2- WO 97/11936 methyl-4- (phenylamino-carbonylmethyl- aminocarbonyl)- 6-(4-propyl- phenyl)hexanoic acid, andcarboxylic acid derivatives Substituted U.S. Pat. No. cyclic 5403952derivatives Thiol WO 98/03166 sulfonamide metalloprotease inhibitorsThiol sulfone WO 98/03164 metalloprotein- ase inhibitors formulations WO97/47296 containing vanadium compounds and N- acetylcysteine NSC-683551; COL-3 (National Cancer Institute) BB-3644 (Neures Ltd.)Arylsulfonamido- CGS- Int Congr 600 mg tid substituted 27023A; InflammRes (Ph I - hydroxamic acids CGS-25966 Assoc 1994 colorectal 7th Abs 73.and EP 606046 melanoma patients); 100 mg/kg in food in osteoarthritismodel rabbits alpha- WO 97/22587 Substituted arylsulfonamido hydroxamicacid derivatives Arylsulfonamido- U.S. Pat. No. active at substituted5455258 30 mg/kg in hydroxamic acids in vivo assay Arylsulfonamido- WO96/00214 substituted hydroxamic acids 2S,3S)-N- WO 98/14424 hydroxy-5-methyl-2-[2-(2- methoxyethoxy) ethoxymethyl[-3- (N-[(1S)-1-(N-methylcarbamoyl)- 2- phenylethyl]carb- amoyl)hexanamide and Hydroxamicacid deriva- tives arylsulfonamido- WO 96/40101 in tumor substitutedmodel mice: hydroxamic acids administered for 7 to 17 days at a dosageof 30 mg/kg twice daily Aryl (sulfide, WO 97/49679 sulfoxide andsulfone) derivatives Phenylsulfon- WO 97/45402 amide derivativesArylsulfonamido- EP 757037 aminoacid derivative A1PDX (Oregon HealthSciences University) futoenone Bio-organic analogs Med Chem Lett 1995 515 1637- 1642 debromohymeni- WO 96/40147 preferred aldisine and 1-30mg/day related compounds amide WO 96/40745 derivatives of 5-amino-1,3,4-thiadiazolones 3S-(4-(N- WO 94/21612 hydroxylamino)- 2R-isobutylsuccinyl) amino-1- methoxymethyl- 3,4- dihydrocarbo- styril andderiviatives therof Carbostyryl JP 8325232 derivatives OPB-3206 (OtsukaPharmaceutical Co, Ltd.) Arylsulfonyl WO 96/33172 hydroxamic acidderivatives Cyclic sulfone EP 816442 derivatives arylsulfonamido WO96/27583 N-hydroxamic acid derivatives of butyric acid Arylsulfonyl- WO98/07697 amino hydroxamic acid derivatives phosphinate- WO 98/03516based derivatives cyclopentyl- WO 92/14706 substituted glutaramidederivatives N-hydroxamic WO 97/49674 acid succinamide derivativesThiadiazole WO 97/48688 amide MMP inhibitors. (S)-1-[2- WO 97/40031[[[(4,5-Dihydro- 5-thioxo-1,3,4- thiadiazol-2- yl)amino]-carbonyl)amino]- 1-oxo-3- (pentafluoro- phenyl)propyl]-4-(2-pyridinyl) - piperazine hydroxamic acid WO 97/32846 derivatives ofpyrrolidone-3- acetamide. alpha- WO 98/17645 arylsulfonamido-N-hydroxamic acid derivatives beta- WO 98/13340 Sulfonylhydrox- amicacids Hydroxamic acid U.S. Pat. No. derivatives 5712300 PNU-99533(Pharmacia & UpJohn Inc.) PNU-143677 (Pharmacia & UpJohn Inc.) POL-641(Poli- farma) Peptidomimetic WO 96/20,18. inhibitors WO 96/29313. WO98/08814. WO 98/08815. WO 98/08850. WO 98/08822. WO 98/08823. WO98/08825. WO 98/08827. 2R)-N- ( )-caprol- WO 96/29313 rheumatoidhydroxycarbox- actam- arthritis: amidedemethyl- (3S)-amine femaledecanoic acid subject - amide of 1N- 50 mg po (carbomethoxy- for 2 yrs;methyl) male subject - 70 mg po daily for 5 yrs; corneal ulcer: malesubject 0 10 mg in saline soln for 2 months, 2 times/day 3-(N-[(N- WO96/20918 Hydroxyamino- carbonyl)methyl]-N- isobutylamino-carbonyl)-2-(R)- isobutylpro- panoyl-L- phenylalanine amide N-hydroxy-WO 98/08853 phosphinic acid amides N′-arylsulfonyl WO 98/08850derivatives of spirocyclic-N- hydroxycarbox- amides N′-arylsulfonyl WO98/08827 derivatives of thiazepinone and azepinone-N- hydroxycarbox-amides Substituted WO 98/08825 piperazine derivatives N′-arylsulfonyl WO98/08823 derivatives of pyrimidine, thiazepine and diazepine-N-hydroxycarbox- amides Substituted WO 98/08815 pyrrolidine derivativesSubstituted WO 98/08814 heterocycles Substituted 1,3- WO 09/08822diheterocyclic derivatives substituted 5- WO 98/25949 amino-1,2,4-thiadiazole-2- thiones Hydroxamic acid WO 97/24117 derivatives whichinhibit TNF production. 6-methoxy- WO 97/37658 1,2,3,4- tetrahydro-norharman-1- carboxylic acid RS-130830 Arthritis Rheum 1997 40 9 SUPPL.S128 Aralkyl MMP WO 96/16027 inhibitors (ex. N-(2R- carboxymethyl-5-(biphen-4- yl)pentanoyl)-L- t-butylglycine- N′-(pyridin-4-yl)carboxamide) Ro-32-3555 (Roche Holding AG) Ro-32-1278 (Roche HoldingAG) Ro-32-1541 (Roche Holding AG) Ro-31-3790 Arthritic (Roche modelrats: Holding Protection AG) of cartilage degradation following oraladministra- tion; ED50 = 10 mg/kg po (3R,11S)-N- WO 95/04735 hydroxy-5-methyl-3-(10- oxo-1,9- diazatricyclo- (11.6.1.014,19) eicosa-13(20),14(19),15, 17-tetraen-11- ylcarbamoyl) hexanamide and derivativesthereof Bridged indoles WO 96/23791 (Roche Holding AG) substituted EP780386 phenylsulfonyl acetamide, propionamide and carboxamide compounds5-(4′-biphenyl)- WO 97/23465 5-[N-(4- nitrophenyl) piperazinyl]barbituric acid Malonic acid EP 716086 based matrix metalloproteinaseinhibitors phenyl WO 95/12603 carboxamide derivatives Malonic acid EP716086 based mmp inhibitors (specifically 2- (4-acetylamino- benzoyl)-4-methylpentanoic acid) Hydroxyl amine Ro-31-4724; EP 236872 derivativesRo-31-7467;

The following individual patent references listed in Table No. 3 below,hereby individually incorporated by reference, describe various MMPinhibitors suitable for use in the present invention described herein,and processes for their manufacture.

TABLE No. 3 MMP inhibitors EP 189784 U.S. Pat. No. 4609667 WO 98/25949WO 98/25580 JP 10130257 WO 98/17655 WO 98/17645 U.S. Pat. No. 5760027U.S. Pat. No. 5756545 WO 98/22436 WO 98/16514 WO 98/16506 WO 98/13340 WO98/16520 WO 98/16503 WO 98/12211 WO 98/11908 WO 98/15525 WO 98/14424 WO98/09958 WO 98/09957 GB 23/18789 WO 98/09940 WO 98/09934 JP 10045699 WO98/08853 WO 98/06711 WO 98/05635 WO 98/07742 WO 98/07697 WO 98/03516 WO98/03166 WO 98/03164 GB 23/17182 WO 98/05353 WO 98/04572 WO 98/04287 WO98/02578 WO 97/48688 WO 97/48685 WO 97/49679 WO 97/47599 WO 97/43247 WO97/43240 WO 97/43238 EP 818443 EP 818442 WO 97/45402 WO 97/40031 WO97/44315 WO 97/38705 U.S. Pat. No. 5679700 WO 97/43245 WO 97/43239 WO97/43237 JP 09227539 WO 97/42168 U.S. Pat. No. 5686419 WO 97/37974 WO97/36580 WO 97/25981 WO 97/24117 U.S. Pat. No. 5646316 WO 97/23459 WO97/22587 EP 780386 DE 19548624 WO 97/19068 WO 97/19075 WO 97/19050 WO97/18188 WO 97/18194 WO 97/18183 WO 97/17088 DE 19542189 WO 97/15553 WO97/12902 WO 97/12861 WO 97/11936 WO 97/11693 WO 97/09066 JP 09025293 EP75/8649 WO 97/03966 WO 97/03783 EP 75/7984 WO 97/02239 WO 96/40745 WO96/40738 WO 96/40737 JP 08/311096 WO 96/40204 WO 96/40147 WO 96/38434 WO96/35714 WO 96/35712 WO 96/35711 WO 96/35687 EP 74,3,070 WO 96/33968 WO96/33165 WO 96/33176 WO 96/33172 WO 96/33166 WO 96/33161 GB 23/00190 WO96/29313 EP 73/6302 WO 96/29307 EP 733369 WO 96/26223 WO 96/27583 WO96/25156 GB 22/98423 WO 96/23791 WO 96/23505 GB 22/97324 DE 19501032 WO96/20918 U.S. Pat. No. 5532265 EP 719770 WO 96/17838 WO 96/16931 WO96/16648 WO 96/16027 EP 716086 WO 96/15096 JP 08104628 WO 96/13523 JP08081443 WO 96/11209 EP 703239 WO 96/06074 WO 95/35276 WO 96/00214 WO95/33731 WO 95/33709 WO 95/32944 WO 95/29892 WO 95/29689 CA 21/16924 WO95/24921 WO 95/24199 WO 95/23790 WO 95/22966 GB 22/87023 WO 95/19965 WO95/19961 WO 95/19956 WO 95/19957 WO 95/13,289 WO 95/13380 WO 95/12603 WO95/09918 WO 95/09841 WO 95/09833 WO 95/09620 WO 95/08327 GB 22/82598 WO95/07695 WO 95/05478 WO 95/04735 WO 95/04033 WO 95/02603 WO 95/02045 EP626378 WO 94/25435 WO 94/25434 WO 94/21612 WO 94/24140 WO 94/24140 EP622079 WO 94/22309 JP 06256209 WO 94/21625 FR 27/03053 EP 606046 WO94/12169 WO 94/11395 GB 22/72441 WO 94/07481 WO 94/04190 WO 94/00119 GB22/68934 WO 94/02446 EP 575844 WO 93/24475 WO 93/24449 U.S. Pat. No.5270326 U.S. Pat. No. 5256657 WO 93/20047 WO 93/18794 WO 93/14199 WO93/14096 WO 93/13741 WO 93/09090 EP 53/2465 EP 532156 WO 93/00427 WO92/21360 WO 92/09563 WO 92/09556 EP 48/9579 EP 489577 U.S. Pat. No.5114953 EP 45/5818 U.S. Pat. No. 5010062 AU 90/53158 WO 97/19075 U.S.Pat. No. 7488460 U.S. Pat. No. 7494796 U.S. Pat. No. 7317407 EP 277428EP 23/2027 WO 96/15096 WO 97/20824 U.S. Pat. No. 5837696

The Marimastat used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in WO 94/02,447.

The Bay-12-9566 used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in WO 96/15,096.

The AG-3340 used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in WO 97/20,824.

The Metastat used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in U.S. Pat. No.5,837,696.

The D-2163 used in the therapeutic combinations of the present inventioncan be prepared in the manner set forth in WO 97/19,075.

More preferred zinc matrix metalloproteinase inhibitors include thosedescribed in the individual U.S. Patent applications, PCT publicationsand U.S. Patents listed below in Table No. 4, and are herebyindividually incorporated by reference.

TABLE No. 4 More preferred zinc matrix metalloproteinase inhibitors U.S.patent application Ser. No. 97/12,873 U.S. patent application Ser. No.97/12,874 U.S. patent application Ser. No. 98/04,299 U.S. patentapplication Ser. No. 98/04,273 U.S. patent application Ser. No.98/04,297 U.S. patent application Ser. No. 98/04,300 U.S. patentapplication Ser. No. 60/119,181 WO 94/02447 WO 96/15096 WO 97/20824 WO97/19075 U.S. Pat. No. 5837696

Even more preferred zinc matrix metalloproteinase inhibitors that may beused in the present invention include:

N-hydroxy-1-(4-methylphenyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

N-hydroxy-1-(phenylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-2,3-dimethoxy-6-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]benzamide;

N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenox]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

British Biotech BB-2516 (Marimastat),N4-[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3(2-methylpropyl)-, [2S-[N4(R*),2R*,3S*]]-);

Bayer Ag Bay-12-9566,4-[(4′-chloro[1,1′-iphenyl]-4-yl)oxy]-2-[(phenylthio)methyl]butanoicacid;

Agouron Pharmaceuticals AG-3340, N-hydroxy-2,2dimethyl-4-[[4-(4-pyridinyloxy)phenyl]-sulfonyl]-3-thiomorpholinecarboxamide;

-   M12) CollaGenex Pharmaceuticals CMT-3 (Metastat),    6-demethyl-6-deoxy-4-dedimethylaminotetracycline;-   M13) Chiroscience D-2163,    2-[1S-([(2R,S)-acetylmercapto-5-phthalimido]pentanoyl-L-leucyl)amino-3-methylbutyl]imidazole;    N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide    monohydrochloride;    N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethbxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide    monohydrochloride;    N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinearboxamide;    1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide    monohydrochloride;    4-[[4-(cyclohexylthio)phenyl]sulfonyl]-N-hydroxy-1-(2-propynyl)-4-piperidinecarboxamide    monohydrochloride;    4-[[4-(4-chlorophenoxy)phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide;    N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide;    1-cyclopropyl-4-[[4-[(4-fluorophenyl)thio]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide;    1-cyclopropyl-N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-4-piperidinecarboxamide;    tetrahydro-N-hydroxy-4-[[4-(4-pyridinylthio)phenyl]sulfonyl]-2H-pyran-4-carboxamide;    tetrahydro-N-hydroxy-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide.

Still more preferred MMP inhibitors include:

N-hydroxy-1-(4-methylphenyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

N-hydroxy-1-(phenylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-2,3-dimethoxy-6-[[4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl]benzamide;

N-hydroxy-1-(4-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-1-(3-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidedihydrochloride;

N-hydroxy-1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamidemonohydrochloride;

British Biotech BB-2516 (Marimastat),N4-[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3(2-methylpropyl)-, [2S-[N4(R*),2R*,3S*]]-);

Bayer Ag Bay-12-9566,4-[(4′-chloro[1,1′-iphenyl]-4-yl)oxy]-2-[(phenylthio)methyl]butanoicacid;

Agouron Pharmaceuticals AG-3340,N-hydroxy-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide;

-   M12) CollaGenex Pharmaceuticals CMT-3 (Metastat),    6-demethyl-6-deoxy-4-dedimethylaminotetracycline;-   M13) Chiroscience D-2163,    2-[1S-([(2R,S)-acetylmercapto-5-phthalimido]pentanoyl-L-leucyl)amino-3-methylbutyl]imidazole.

Also included in the combination of the invention are the isomeric formsand tautomers of the described compounds and thepharmaceutically-acceptable salts thereof. Illustrative pharmaceuticallyacceptable salts are prepared from formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic,b-hydroxybutyric, galactaric and galacturonic acids.

Suitable pharmaceutically-acceptable base addition salts of compounds ofthe present invention include metallic ion salts and organic ion salts.More preferred metallic ion salts include, but are not limited toappropriate alkali metal (group Ia) salts, alkaline earth metal (groupIIa) salts and other physiological acceptable metal ions. Such salts canbe made from the ions of aluminum, calcium, lithium, magnesium,potassium, sodium and zinc. Preferred organic salts can be made fromtertiary amines and quaternary ammonium salts, including in part,trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of the above salts can be preparedby those skilled in the art by conventional means from the correspondingcompound of the present invention.

A MMP inhibitor of the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa. 1975. Another discussion of drug formulations can be foundin Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are solid at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, a contemplated aromatic sulfone hydroximateinhibitor compound can be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, gelatin, acacia gum, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thentableted or encapsulated for convenient administration. Such capsules ortablets can contain a controlled-release formulation as can be providedin a dispersion of active compound in hydroxypropylmethyl cellulose. Inthe case of capsules, tablets, and pills, the dosage forms can alsocomprise buffering agents such as sodium citrate, magnesium or calciumcarbonate or bicarbonate. Tablets and pills can additionally be preparedwith enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. A contemplated MMP inhibitor compound can be dissolvedin water, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

Dosage of MMP Inhibitors

Dosage levels of MMP inhibitors on the order of about 0.1 mg to about10,000 mg of the active ingredient compound are useful in the treatmentof the above conditions, with preferred levels of about 1.0 mg to about1,000 mg. The amount of active ingredient that may be combined withother anticancer agents to produce a single dosage form will varydepending upon the host treated and the particular mode ofadministration.

It is understood, however, that a specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, rate of excretion, drug combination,and the severity of the particular disease being treated and form ofadministration.

Treatment dosages generally may be titrated to optimize safety andefficacy. Typically, dosage-effect relationships from in vitro initiallycan provide useful guidance on the proper doses for patientadministration. Studies in animal models also generally may be used forguidance regarding effective dosages for treatment of cancers inaccordance with the present invention. In terms of treatment protocols,it should be appreciated that the dosage to be administered will dependon several factors, including the particular agent that is administered,the route administered, the condition of the particular patient, etc.Generally speaking, one will desire to administer an amount of thecompound that is effective to achieve a serum level commensurate withthe concentrations found to be effective in vitro. Thus, where ancompound is found to demonstrate in vitro activity at, e.g., 10 μM, onewill desire to administer an amount of the drug that is effective toprovide about a 10 μM concentration in vivo. Determination of theseparameters are well within the skill of the art.

These considerations, as well as effective formulations andadministration procedures are well known in the art and are described instandard textbooks.

The phrase “antineoplastic agents” includes agents that exertantineoplastic effects, i.e., prevent the development, maturation, orspread of neoplastic cells, directly on the tumor cell, e.g., bycytostatic or cytocidal effects, and not indirectly through mechanismssuch as biological response modification. There are large numbers ofantineoplastic agents available in commercial use, in clinicalevaluation and in pre-clinical development, which could be included inthe present invention for treatment of neoplasia by combination drugchemotherapy. For convenience of discussion, antineoplastic agents areclassified into the following classes, subtypes and species:

ACE inhibitors,

alkylating agents,

angiogenesis inhibitors,

angiostatin,

anthracyclines/DNA intercalators,

anti-cancer antibiotics or antibiotic-type agents,

antimetabolites,

antimetastatic compounds,

asparaginases,

bisphosphonates,

cGMP phosphodiesterase inhibitors,

calcium carbonate,

cyclooxygenase-2 inhibitors

DHA derivatives,

DNA topoisomerase,

endostatin,

epipodophylotoxins,

genistein,

hormonal anticancer agents,

hydrophilic bile acids (URSO),

immunomodulators or immunological agents,

integrin antagonists

interferon antagonists or agents,

MMP inhibitors,

miscellaneous antineoplastic agents,

monoclonal antibodies,

nitrosoureas,

NSAIDs,

ornithine decarboxylase inhibitors,

pBATTs,

radio/chemo sensitizers/protectors,

retinoids

selective inhibitors of proliferation and migration of endotheliaicells,

selenium,

stromelysin inhibitors,

taxanes,

vaccines, and

vinca alkaloids.

The major categories that some preferred antineoplastic agents fall intoinclude antimetabolite agents, alkylating agents, antibiotic-typeagents, hormonal anticancer agents, immunological agents,interferon-type agents, and a category of miscellaneous antineoplasticagents. Some antineoplastic agents operate through multiple or unknownmechanisms and can thus be classified into more than one category.

A first family of antineoplastic agents which may be used in combinationwith the present invention consists of antimetabolite-typeantineoplastic agents. Antimetabolites are typically reversible orirreversible enzyme inhibitors, or compounds that otherwise interferewith the replication, translation or transcription of nucleic acids.Suitable antimetabolite antineoplastic agents that may be used in thepresent invention include, but are not limited to acanthifolic acid,aminothiadiazole, anastrozole, bicalutamide, brequinar sodium,capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates,cytarabine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezaguanine,dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine,Wellcome EHNA, Merck & Co. EX-015, fazarabine, finasteride, floxuridine,fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil, Daiichi SeiyakuFO-152, fluorouracil (5-FU), 5-FU-fibrinogen, isopropyl pyrrolizine,Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, WellcomeMZPES, nafarelin, norspermidine, nolvadex, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, stearate;Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, TaihoUFT, toremifene, and uricytin.

Preferred antimetabolite agents that may be used in the presentinvention include, but are not limited to, those identified in Table No.5, below.

TABLE No. 5 Antimetabolite agents Common Name/ Compound Trade NameCompany Reference Dosage 1,3- anastrozole; Zeneca EP 296749 1-mg/Benzenediaceto- ARIMIDEX ® day nitrile, alpha, alpha, alpha′, alpha′-tetramethyl-5- (1H-1,2,4- triazol-1-yl- methyl)- Propanamide,bicalutamide; Zeneca EP 100172 50 mg N-[4-cyano-3- CASODEX ® once(trifluoromethyl) daily phenyl)-3- [(4- fluorophenyl) sulfonyl]-2-hydroxy-2- methyl-, (+/−)- capecitabine Roche U.S. Pat. No. 5472949Adenosine, 2- cladribine; Johnson & EP 173059 0.09 chloro-2′- 2-CdA;Johnson mg/kg/ deoxy-; 2- LEUSTAT; day chloro-2′- LEUSTA- for 7deoxy-(beta)- TIN ® days. D-adenosine) LEUSTA-TIN ® in-jection;LEUSTATINE ®; RWJ- 26251; 2(1H)- cytarabine Yamasa EP 239015 100-Pyrimidione, ocfosfate; Corp 300 4-amino-1-[5- ara CMP mg/day O- stearylfor [hydroxy(octa- ester; C- 2 weeks decyloxy)phos- 18-PCA;phinyl]-beta-D- cytarabine arabinofuran- phosphate osyl]- stearate;monosodium Starasid; salt YNK-O1; CYTOSAR-U ® 4-Azaandrost- finasteride;Merck & EP 155096 1-ene-17- PROPECIA ® Co carboxamide, N-(1,1-diethylethyl) -3-oxo- (5alpha, 17beta)- fluorouracil U.S. Pat. No.(5-FU) 4336381 Fludarabine fludarabine Southern U.S. Pat. No. 25 mg/phosphate. phosphate; Research 4357324 m²/d 9H-Purin-6- 2-F-araAMP;Institute; IV over amine, 2- Fludara; Berlex a period fluoro-9-(5-O-Fludara iv; of phosphono- Fludara approxi- beta-D- Oral; NSC- matelyarabinofuran- 312887; SH- 30 osyl) 573; SH- minutes 584; SH- daily 586;for 5 consec- utive days com- menced every 28 days. gemcit- Eli LilyU.S. Pat. No. abine 4526988 N-(4-(((2,4- methotrexate Hyal U.S. Pat. No.tropho- diamino-6- iv, Hyal; Pharma- 2512572 blastic pteridinyl) HA +ceutical; diseases: methyl)methyl- methotrexate, American 15 to 30amino)benzoyl)-L- Hyal; Home mg/d glutamic acid methotrexate Products;orally or iv, HIT Lederle intra- Technolog; muscularly in a five- daycourse (repeated 3 to 5 times as needed) Luteinizing nafarelin Roche EP21234 hormone- releasing factor (pig), 6-[3-(2- napthalenyl)-D-alanine]- pentostatin; Warner- U.S. Pat. No. CI-825; Lambert 3923785DCF; deoxycofor- mycin; Nipent; NSC-218321; Oncopent; Ethanamine, 2-toremifene; Orion EP 95875 60 mg/d [4-(4-chloro- FARESTON ® Pharma1,2-diphenyl- 1- butenyl)phenoxy]- N,N-dimethyl- (Z)-

A second family of antineoplastic agents which may be used incombination with the present invention consists of alkylating-typeantineoplastic agents. The alkylating agents are believed to act byalkylating and cross-linking guanine and possibly other bases in DNA,arresting cell division. Typical alkylating agents include nitrogenmustards, ethyleneimine compounds, alkyl sulfates, cisplatin, andvarious nitrosoureas. A disadvantage with these compounds is that theynot only attack malignant cells, but also other cells which arenaturally dividing, such as those of bone marrow, skin,gastro-intestinal mucosa, and fetal tissue. Suitable alkylating-typeantineoplastic agents that may be used in the present invention include,but are not limited to, Shionogi 254-S, aldo-phosphamide analogues,altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,budotitane, Wakunaga CA-102, carboplatin, carmustine (BiCNU),Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide,American Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarbazine,Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinumcytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09,elmustine, Erbamont FCE-24517, estramustine phosphate sodium, etoposidephosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam,ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol,mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, thiotepa, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol.

Preferred alkylating agents that may be used in the present inventioninclude, but are not limited to, those identified in Table No. 6, below.

TABLE No. 6 Alkylating agents Common Name/ Compound Trade Name CompanyReference Dosage Platinum, carboplatin; Johnson U.S. Pat. No. 360 mg/ml4657927. diammine PARA- Matthey U.S. Pat. No. (squared) [1,1-cyclo-PLATIN ® 4140707. I.V. on butanedi- day 1 carboxylato every 4 (2-)]-,weeks. (SP-4-2)- Carmustine, BiCNU ® Ben Venue JAMA 1985; Preferred:1,3-bis (2- Labora- 253 (11): 150 to 200 chloroethyl) tories, 1590-1592.mg/m² -1-nitro- Inc. every 6 sourea wks. etoposide Bristol- U.S. Pat.No. phosphate Myers 4564675 Squibb thiotepa Platinum, cisplatin;Bristol- U.S. Pat. No. diamminedi- PLATINOL- Myers 4177263 chloro-, AQSquibb (SP-4-2)- dacarbazine DTIC Dome Bayer 2 to 4.5 mg/kg/day for 10days; 250 mg/ square meter body surface/ day I.V. for 5 days every 3weeks ifosfamide IFEX Bristol- 4-5 g/m Meyers (square) Squibb singlebolus dose, or 1.2-2 g/m (square) I.V. over 5 days. cyclophos- U.S. Pat.No. phamide 4537883 cis- Platinol Bristol- 20 mg/M² diaminedi- CisplatinMyers IV daily chloro- Squibb for a 5 platinum day cycle.

A third family of antineoplastic agents which may be used in combinationwith the present invention consists of antibiotic-type antineoplasticagents. Suitable antibiotic-type antineoplastic agents that may be usedin the present invention include, but are not limited to Taiho 4181-A,aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

Preferred antibiotic anticancer agents that may be used in the presentinvention include, but are not limited to, those agents identified inTable No. 7, below.

TABLE No. 7 Antibiotic anticancer agents Common Name/ Compound TradeName Company Reference Dosage 4-Hexenoic mycopheno- Roche WO 91/19498 1to 3 gm/d acid, 6-(1,3- late mofetil dihydro-4- hydroxy-6- methoxy-7-methyl-3- oxo-5- isobenzo- furanyl)-4- methyl-, 2- (4- morpholinyl)ethyl ester, (E)- mitoxan- U.S. Pat. No. trone 4310666 doxorubicin U.S.Pat. No. 3590028 Mitomycin Mutamycin Bristol- After full and/or Myershemato- mitomycin-C Squibb logical Oncology/ recovery Immun- from anyology previous chemo- therapy: 20 mg/m² intra- venously as a single dosevia a function- ing intra- venous catheter.

A fourth family of antineoplastic agents which may be used incombination with the present invention consists of syntheticnucleosides. Several synthetic nucleosides have been identified thatexhibit anticancer activity. A well known nucleoside derivative withstrong anticancer activity is 5-fluorouracil (5-FU). 5-Fluorouracil hasbeen used clinically in the treatment of malignant tumors, including,for example, carcinomas, sarcomas, skin cancer, cancer of the digestiveorgans, and breast cancer. 5-Fluorouracil, however, causes seriousadverse reactions such as nausea, alopecia, diarrhea, stomatitis,leukocytic thrombocytopenia, anorexia, pigmentation, and edema.Derivatives of 5-fluorouracil with anti-cancer activity have beendescribed in U.S. Pat. No. 4,336,381. Further 5-FU derivatives have beendescribed in the following patents listed in Table No. 8, herebyindividually incorporated by reference herein.

TABLE No. 8 5-Fu derivatives JP 50-50383 JP 50-50384 JP 50-64281 JP51-146482 JP 53-84981

U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation productof inosine, adenosine, or cytidine with methanol or ethanol has activityagainst lymphocytic leukemia. Cytosine arabinoside (also referred to asCytarabin, araC, and Cytosar) is a nucleoside analog of deoxycytidinethat was first synthesized in 1950 and introduced into clinical medicinein 1963. It is currently an important drug in the treatment of acutemyeloid leukemia. It is also active against acute lymphocytic leukemia,and to a lesser extent, is useful in chronic myelocytic leukemia andnon-Hodgkin's lymphoma. The primary action of araC is inhibition ofnuclear DNA synthesis. Handschumacher, R. and Cheng, Y., “Purine andPyrimidine Antimetabolites”, Cancer Medicine, Chapter XV-1, 3rd Edition,Edited by J. Holland, et al., Lea and Febigol, publishers.

5-Azacytidine is a cytidine analog that is primarily used in thetreatment of acute myelocytic leukemia and myelodysplastic syndrome.

2-Fluoroadenosine-5′-phosphate (Fludara, also referred to as FaraA) isone of the most active agents in the treatment of chronic lymphocyticleukemia. The compound acts by inhibiting DNA synthesis. Treatment ofcells with F-araA is associated with the accumulation of cells at theG1/S phase boundary and in S phase; thus, it is a cell cycle Sphase-specific drug. InCorp of the active metabolite, F-araATP, retardsDNA chain elongation. F-araA is also a potent inhibitor ofribonucleotide reductase, the key enzyme responsible for the formationof DATP. 2-Chlorodeoxyadenosine is useful in the treatment of low gradeB-cell neoplasms such as chronic lymphocytic leukemia, non-Hodgkins'lymphoma, and hairy-cell leukemia. The spectrum of activity is similarto that of Fludara. The compound inhibits DNA synthesis in growing cellsand inhibits DNA repair in resting cells.

A fifth family of antineoplastic agents which may be used in combinationwith the present invention consists of hormonal agents. Suitablehormonal-type antineoplastic agents that may be used in the presentinvention include, but are not limited to Abarelix; Abbott A-84861;Abiraterone acetate; Aminoglutethimide; anastrozole; Asta Medica AN-207;Antide; Chugai AG-041R; Avorelin; aseranox; Sensus B2036-PEG;Bicalutamide; buserelin; BTG CB-7598; BTG CB-7630; Casodex; cetrolix;clastroban; clodronate disodium; Cosudex; Rotta Research CR-1505;cytadren; crinone; deslorelin; droloxifene; dutasteride; Elimina; LavalUniversity EM-800; Laval University EM-652; epitiostanol; epristeride;Mediolanum EP-23904; EntreMed 2-ME; exemestane; fadrozole; finasteride;flutamide; formestane; Pharmacia & Upjohn FCE-24304; ganirelix;goserelin; Shire gonadorelin agonist; Glaxo Wellcome GW-5638; HoechstMarion Roussel Hoe-766; NCI hCG; idoxifene; isocordoin; ZenecaICI-182780; Zeneca ICI-118630; Tulane University J015X; Schering Ag J96;ketanserin; lanreotide; Milkhaus LDI-200; letrozol; leuprolide;leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide;mepitiostane; Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447;LG-2293; LG-2527; LG-2716; Bone Care International LR-103; LillyLY-326315; Lilly LY-353381-HCl; Lilly LY-326391; Lilly LY-353381; LillyLY-357489; miproxifene phosphate; Orion Pharma MPV-2213ad; TulaneUniversity MZ-4-71; nafarelin; nilutamide; Snow Brand NKS01; octreotide;Azko Nobel ORG-31710; Azko Nobel ORG-31806; orimeten; orimetene;orimetine; ormeloxifene; osaterone; Smithkline Beecham SKB-105657; TokyoUniversity OSW-1; Peptech PTL-03001; Pharmacia & Upjohn PNU-156765;quinagolide; ramorelix; Raloxifene; statin; sandostatin LAR; ShionogiS-10364; Novartis SMT-487; somavert; somatostatin; tamoxifen; tamoxifenmethiodide; teverelix; toremifene; triptorelin; TT-232; vapreotide;vorozole; Yamanouchi YM-116; Yamanouchi YM-511; Yamanouchi YM-55208;Yamanouchi YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211; andZeneca ZD-182780.

Preferred hormonal agents that may be used in the present inventioninclude, but are not limited to, those identified in Table No. 9, below.

TABLE 9 Hormonal agents Common Name/ Compound Trade Name CompanyReference Dosage 2- EntreMed; EntreMed methoxyestradiol 2-Me N-(S)-A-84861 Abbott tetrahydrofuroyl- Gly-D2Nal- D4ClPhe-D3Pal- Ser-NMeTyr-DLys(Nic)-Leu- Lys(Isp)-Pro- DAla-NH2 raloxi- fene [3R-1-(2,2- AG-041RChugai WO Dimethoxyethyl)- 94/19322 3-((4-methylphenyl) aminocarbonyl-methyl)-3-(N′- (4-methylphenyl) ureido)-indoline- 2-one] AN-207 Asta WOMedica 97/19954 Ethanamine, 2- toremifene; Orion EP 95875 60 mg/d[4-(4-chloro- FARES- Pharma 1,2-diphenyl-1- TON ® butenyl)phenoxy]-N,N-dimethyl-,(Z)- Ethanamine, 2- tamoxifen Zeneca US For [4-(1,2-NOLVA- 4536516 patients diphenyl-1- DEX(R) with butenyl)phenoxy]- breastN,N-dimethyl-,(Z)- cancer, the recom- mended daily dose is 20-40 mg.Dosages greater than 20 mg per day should be divided (morn- ing andeven- ing). D-Alaninamide N- Antide; Ares- WO 25 or acetyl-3-(2-ORF-23541 Serono 89/01944 50 naphthalenyl)-D- microg/ alanyl-4-chloro-kg sc D-phenylalanyl- 3-(3- pyridinyl)-D- alanyl-L-seryl- N6-(3-pyridinylcarbonyl)- L-lysyl-N6- (3-pyridinyl- carbonyl)- D-lysyl-L-leucyl-N6-(1- methylethyl)-L- lysyl-L-prolyl- B2036- Senus PEG; Somaver;Trovert 4-Methyl-2-[4- EM-800; Laval [2-(1- EM-652 Universitypiperidinyl)ethoxy] phenyl]-7- (pivaloyloxy)-3- [4-(pivaloyloxy)phenyl]-2H-1- benzopyran letrozol US 4749346 goserelin US 41002743-[4-[1,2- GW-5638 Glaxo Diphenyl-1(Z)- Wellcome butenyl]phenyl]-2(E)-propenoic acid Estra-1,3,5(10)- ICI- Zeneca EP 34/6014 250 mg/triene-3,17- 182780; mth diol, 7-[9- Faslodex; [(4,4,5,5,5- ZD-182780pentafluoro- pentyl) sulfinyl]- nonyl]-, (7alpha,17beta)- J015X TulaneUniversity LG-1127; Ligand LG-1447 Pharma- ceuticals LG-2293 LigandPharma- ceuticals LG-2527; Ligand LG-2716 Pharma- ceuticals buser-Peptech elin, Peptech; des- lorelin, Peptech; PTL- 03001; trip- torelin,Peptech LR-103 Bone Care Interna- tional [2-(4- LY-326315 Lilly WOHydroxyphenyl)- 9609039 6- hydroxynaphthalen- 1-yl] [4-[2- (1-piperdinyl)ethoxy] phenyl] methane hydrochloride LY- Lilly 353381- HClLY-326391 Lilly LY-353381 Lilly LY-357489 Lilly MPV- Orion EP 4769440.3-300 2213ad Pharma mg Isobutyryl-Tyr- MZ-4-71 Tulane D-Arg-Asp-Ala-University Ile-(4-Cl)-Phe- Thr-Asn-Ser-Tyr- Arg-Lys-Val-Leu- (2-aminobutyryl)- Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu- Gln-Asp-Ile-Nle- Ser 4-guanidinobutyl- amide Androst-4-ene- NKS01; Snow EP 3000623,6,17-trione, 14alpha- Brand 14-hydroxy- OHAT; 14OHAT 3beta,16beta,OSW-1 17alpha- trihydroxycholest- 5-en-22-one- 16-O-(2-0-4-methoxybenzoyl- beta-D-xylopyran- osyl)-(1-3) (2-0- acetyl-alpha-L-arabinopyranoside) Spiro[estra-4,9- Org- Akzo EP 289073 diene- 31710;Nobel 17,2′(3′H)- Org-31806 furan]-3-one, 11-[4- (dimethylamino)phenyl]-4′,5′- dihydro-6- methyl-, (6beta,11beta,17 beta)-(22RS)-N-(1,1,1- PNU- Pharmacia trifluoro-2- 156765; & phenylprop-2-FCE-28260 Upjohn yl)-3-oxo-4-aza- 5alpha-androst- 1-ene-17beta-carboxamide 1-[(benzofuran- Menarini 2yl)-4- chlorophenylmethyl]imidazole Tryptamine Rhone- WO derivatives Poulenc 96/35686 RorerPermanently Pharmos WO ionic 95/26720 derivatives of steroid hormonesand their antagonists Novel Meiji WO tetrahydronaphtho- Seika 97/30040furanone derivatives SMT-487; Novartis 90Y- octreo- tideD-Phe-Cys-Tyr-D- TT-232 Trp-Lys-Cys-Thr- NH2 2-(1H-imidazol- YM-116Yaman- 4-ylmethyl)-9H- ouchi carbazole monohydrochloride monohydrate4-[N-(4- YM-511 Yaman- bromobenzyl)-N- ouchi (4- cyanophenyl)amino]-4H-1,2,4- triazole 2-(1H-imidazol- YM-55208; Yaman-4-ylmethyl)-9H- YM-53789 ouchi carbazole monohydrochloride monohydrateZK- Schering 1911703 AG ZK- Schering 230211 AG abarelix Praecis Pharma-ceuticals Androsta-5,16- abira- BTG dien-3-ol, 17- terone(3-pyridinyl)-, acetate; acetate (ester), CB-7598; (3beta)- CB-7630 2,6-amino- Novartis US 3944671 Piperidinedione, glutethimide; 3-(4- Ciba-aminophenyl)-3- 16038; ethyl- Cytadren; Elimina; Orimeten; Orimetene;Orimetine 1,3- anastro- Zeneca EP 296749 1 mg/ Benzenediacetoni- zole;day trile,alpha,alpha, Arimidex; alpha′,alpha′- ICI- tetramethyl-5-D1033; (1H-1,2,4- ZD-1033 triazol-1-ylmethyl)- 5-Oxo-L-prolyl- avorelin;Medi- EP 23904 L-histidyl-L- Meterelin olanum tryptophyl-L-seryl-L-tyrosyl- 2-methyl-D- tryptophyl-L- leucyl-L- arginyl-N-ethyl-L-prolinamide Propanamide, N- bicalutamide; Zeneca EP 100172 [4-cyano-3-Casodex; (trifluoromethyl) Cosudex; phenyl]-3-[(4- ICI- fluorophenyl)176334 sulfonyl]-2- hydroxy-2- methyl-, (+/−)- Luteinizing busere-Hoechst GB 200- hormone- lin; Hoe- Marion 15/23623 600 releasing factor766; Roussel microg/ (pig), 6-[O- Profact; day (1,1- Receptal;dimethylethyl)- S-746766; D-serine]-9-(N- Suprecor; ethyl-L- Suprecur;prolinamide)-10- Supre- deglycinamide- fact; Suprefakt D-Alaninamide,cetro- Asta EP 29/9402 N-acetyl-3-(2- relix; Medica naphthalenyl)-D-SB-075; alanyl-4-chloro- SB-75 D-phenylalanyl- 3-(3-pyridinyl)-D-alanyl-L- seryl-L-tyrosyl- N5- (aminocarbonyl)- D-ol-L-leucyl-L-arginyl-L- prolyl- Phosphonic acid, clodro- Schering (dichloromethylene)nate AG bis-, disodium, disodium salt- Leiras; Bonefos; Clastoban;KCO-692 Luteninizing deslorelin; Roberts US hormone- gonado- 4034082releasing factor relin (pig), 6-D- analogue, tryptophan-9-(N- Roberts;ethyl-L- LHRH prolinamide)-10- analogue, deglycinamide- Roberts;Somagard Phenol, 3-[1-[4- droloxi- Klinge EP 54168 [2- fene; FK-(dimethylamino) 435; K- ethoxy]phenyl]-2- 060; K- phenyl-1- 21060E;butenyl]-, (E)- RP 60850 [CA S] 4-Azaandrost-1- dutaster- Glaxo ene-17-ide; GG- Wellcome carboxamide, N- 745; GI- (2,5- 198745bis(trifluoromethyl) phenyl)-3- oxo-, (5alpha, 17beta)- Androstan-17-ol,epitio- Shionogi US 3230215 2,3-epithio-, stanol; (2alpha,3alpha,10275-S; 5alpha,17beta)- epithiondro- stanol; S- 10275; Thiobres- tin;Thiodrol Androsta-3,5- epriste- Smith- EP 289327 0.4-160 diene-3- ride;Kline mg/day carboxylic acid, ONO-9302; Beecham 17-(((1,1- SK&F-dimethylethyl) 105657; amino)carbonyl)- SKB- (17beta)- 105657 estrone3-O- estrone sulfamate 3-O- sulfamate 19-Norpregna- ethinyl Schering DE1949095 1,3,5(10)-trien- estradiol AG 20-yne-3,17- sulfon- diol, 3-(2-ate; J96; propanesulfonate), Turisteron (17alpha)- Androsta-1,4- exemes-Pharmacia DE 3622841 5 mg/kg diene-3,17- tane; & dione, 6- FCE-24304Upjohn methylene Benzonitrile, 4- fadrozo- Novartis EP 165904 1 mg(5,6,7,8- le; po bid tetrahydroimidazo Afema; [1,5-a]pyridin- Arensin;5-yl)-, CGS- monohydrochloride 16949; CGS- 16949A; CGS- 20287; fadrozolemonohydro- chloride 4-Azaandrost-1- finaster- Merck & EP 155096 5 mg/ene-17- ide; Co day carboxamide, N- Andozac; (1,1- ChibroProdimethylethyl)- scar; 3-oxo-, Finastid; (5alpha,17beta)- MK-0906;MK-906; Procure; Prodel; Propecia; Proscar; Proskar; Prostide; YM-152Propanamide, 2- Flutamide; Schering US 4329364 methyl-N-[4- Drogenil;Plough nitro-3- Euflex; (trifluoromethyl) Eulexin; phenyl]- Eulexine;Flucinom; Flutamida; Fugerel; NK-601; Odyne; Prostogenat; Sch-13521Androst-4-ene- formest- Novartis EP 346953 250 or 3,17-dione, 4- ane; 4-600 mg/ hydroxy- Had; 4- day po OHA; CGP- 32349; CRC- 82/01; Depot;Lentaron [N-Ac-D-Nal,D- ganirelix; Roche EP 312052 pCl-Phe,D-Pal,D-Org-37462; hArg(Et)2,hArg(Et) RS-26306 2,D-Ala]GnRH- gonadorelin Shireagonist, Shire Luteinizing goserelin; Zeneca US 4100274 hormone- ICI-releasing factor 118630; (pig), 6-[O- Zoladex; (1,1- Zoladexdimethylethyl)- LA D-serine]-10- deglycinamide-, 2- (aminocarbonyl)hydrazide hCG; Milkhaus gonadotro- phin; LDI-200 human NIH chorionicgonadotro- phin; hCG Pyrrolidine, 1- idoxifene; BTG EP 260066[2-[4-[1-(4- CB-7386; iodophenyl)-2- CB-7432; phenyl-1- SB-223030butenyl]phenoxy] ethyl]-, (E)- isocordoin Indena 2,4(1H,3H)- ketanse-Johnson EP 13612 Quinazolinedione, rin; & 3-[2-[4-(4- Aseranox; Johnsonfluorobenzoyl)- Ketensin; 1- KJK-945; piperidinyl] ketanse- ethyl]-rine; Perketan; R-41468; Serefrex; Serepress; Sufrexal; TaseronL-Threoninamide, lanreotide; Beaufour- EP 215171 3-(2- Angiopeptin;Ipsen naphthalenyl)-D- BIM- alanyl-L- 23014; cysteinyl-L- Dermopeptin;tyrosyl-D- Ipstyl; tryptophyl-L- Somatuline; lysyl-L-valyl-L- Somatulinecysteinyl-, LP cyclic (2-7)- disulfide Benzonitrile, letrozole; NovartisEP 236940 2.5 mg/ 4,4′-(1H-1,2,4- CGS-20267; day triazol-1- Femaraylmethylene)bis- Luteinizing leuprolide, Atrix hormone- Atrigel;releasing factor leuprolide, (pig), 6-D- Atrix leucine-9-(N- ethyl-L-prolinamide)- 10- deglycinamide- Luteinizing Leuprore- Abbott US 40050633.75 hormone- lin; microg releasing factor Abbott- sc q 28 (pig), 6-D-43818; days leucine-9-(N- Carcinil ethyl-L- Enantone; prolinamide)-10-Leuplin; deglycinamide- Lucrin; Lupron; Lupron Depot; leuprolide,Abbott; leuprolide, Takeda; leuprorelin, Takeda; Procren Depot; Procrin;Prostap; Prostap SR; TAP- 144-SR Luteinizing leuprore- Alza hormone-lin, releasing factor DUROS; (pig), 6-D- leuprolide, leucine-9-(N-DUROS; ethyl-L- leuprore- prolinamide)- lin 10- deglycinamide- 1H-liaro- Johnson EP 260744 300 mg Benzimidazole, zole; & bid 5-[(3-Liazal; Johnson chlorophenyl)- Liazol; 1H-imidazol-1- liarozoleylmethyl]- fumarate; R-75251; R-85246; Ro-85264 Urea, N′- lisuride VUFB[(8alpha)-9,10- hydrogen didehydro-6- maleate; methylergolin-8- Cuvalit;yl]-N,N-diethyl-, Dopergin; (Z)-2- Dopergine; butenedioate Eunal; (1:1)Lysenyl; Lysenyl Forte; Revanil Pentanoic acid, loxiglumide; Rotta WO4-[(3,4- CR-1505 Research 87/03869 dichlorobenzoyl) amino]-5-[(3-methoxypropyl) pentylamino]-5- oxo-, (+/−)- Androstane, 2,3-mepitiostane; Shionogi US 3567713 epithio-17-[(1- S-10364; methoxycyclo-Thioderon pentyl)oxy]-, (2alpha,3alpha,5 alpha,17beta)- Phenol, 4-[1-[4-miproxifene Taiho WO 20 mg/ [2- phosphate; 87/07609 day (dimethylamino)DP-TAT- ethoxy]phenyl]-2- 59; TAT-59 [4-(1- methylethyl) phenyl]-1-butenyl]-, dihydrogen phosphate (ester), (E)- Luteinizing nafarelin;Roche EP 21/234 hormone- NAG, releasing factor Syntex; (pig), 6-[3-(2-Nasanyl; naphthalenyl)-D- RS-94991; alanine]- RS-94991- 298; Synarel;Synarela; Synrelina 2,4- nilutamide; Hoechst US 4472382Imidazolidinedione, Anandron; Marion 5,5- Nilandron; Rousseldimethyl-3-[4- Notostran; nitro-3- RU-23908 (trifluoromethyl) pheyl]-obesity Lilly WO gene; 96/24670 diabetes gene; leptin L-Cysteinamide,octreotide; Novartis EP 29/579 D-phenylalanyl- Longastatina;L-cysteinyl-L- octreotide phenylalanyl-D- pamoate; tryptophyl-L-Sandostatin; lysyl-L- Stadostatin threonyl-N-[2- LAR; hydroxy-1-Sandostatina; (hydroxymethyl) Sandostatine; propyl]-, cyclic SMS-201-995(2-7)- disulfide, [R- (R*,R*)]- Pyrrolidine, 1- ormelox- Central DE2329201 [2-(p-(7- ifene; Drug methoxy-2,2- 6720- Research dimethyl-3-CDRI; Inst. phenyl-4- Centron; chromanyl) Choice-7; phenoxy)ethyl]-,centchroman; trans- Saheli 2-Oxapregna-4,6- osaterone Teikoku EP 193871diene-3,20- acetate; Hormone dione, 17- Hipros; (acetyloxy)-6- TZP-4238chloro- Pregn-4-ene- progesterone; Columbia 3,20-dione Crinone Labora-tories Sulfamide, N,N- quinagolide; Novartis EP 77754 diethyl-N′- CV-(1,2,3,4,4a,5,10, 205-502; 10a-octahydro- Norprolac; 6-hydroxy-1-SDZ-205- propylbenzo[g] 502 quinolin-3-yl)-, (3alpha,4aalpha, 10abeta)-(+/−)- L-Proline, 1- ramore- Hoechst EP 451791 (N2-(N-(N-(N-(N- lix;Hoe- Marion (N-(N-(N-acetyl- 013; Hoe- Roussel 3-(2- 013C;naphthalenyl)-D- Hoe-2013 alanyl)-4-chloro- D-phenylalanyl)-D-tryptophyl)-L- seryl)-L- tyrosyl)-O-(6- deoxy-alpha-L-mannopyranosyl)- D-seryl)- L-leucyl)-L- arginyl)-, 2- (aminocarbonyl)hydrazide- somatostatin Tulane analogues University Ethanamine, 2-taxomi- Zeneca US 4536516 [4-(1,2- fen; diphenyl-1- Ceadan;butenyl)phenoxy]- ICI- N,N-dimethyl-, 46474; (Z)- Kessar; Nolgen;Nolvadex; Tafoxen; Tamofen; Tamoplex; Tamoxasta; Tamoxen; Tomaxentamoxifen Pharmos methiodide Ethanamine, 2- tamoxifen Douglas [4-(1,2-diphenyl-1- butenyl)phenoxy]- N,N-dimethyl-, (z)- D-Alaninamide, tevere-Asta N-acetyl-3-(2- lix; Medica naphthalenyl)-D- Antarelixalanyl-4-chloro- D-phenylalanyl- 3-(3-pyridinyl)- D-alanyl-L-seryl-L-tyrosyl- N6- (aminocarbonyl)- D-lysyl-L- leucyl-N6-(1-methylethyl)-L- lysyl-L-prolyl- Ethanamine, 2- toremifene; Orion EP95875 60 mg [4-(4-chloro- Estrimex Pharma po 1,2-diphenyl-1- Fareston;butenyl)phenoxy]- FC-1157; N,N-dimethyl-, FC-1157a; (Z)- NK-622Luteinizing tripto- Debio- US 4010125 hormone- relin; pharm releasingfactor ARVEKAP; (pig), 6-D- AY-25650; tryptophan- BIM- 21003; BN-52104;Decapeptyl; WY-42422 L- vapreotide; Debio- EP 203031 500Tryptophanamide, BMY-41606; pharm microg D-phenylalanyl- Octastatin; sctid L-cysteinyl-L- RC-160 tyrosyl-D- tryptophyl-L- lysyl-L-valyl-L-cysteinyl-, cyclic (2-7)- dsulfide- 1H- vorozole; Johnson EP 2939782.5 mg/ Benzotriazole, R-76713; & day 6-[(4- R-83842; Johnsonchlorophenyl)- Rivizor 1H-1,2,4- triazol-1- ylmethyl]-1- methyl-

A sixth family of antineoplastic agents which may be used in combinationwith the present invention consists of a miscellaneous family ofantineoplastic agents including, but not limited to alpha-carotene,alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52,alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin,anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-MyersBMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, WellcomeBW-773, calcium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane calciumcarbonate tablets, caracemide, carmethizole hydrochloride, AjinomotoCDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Cell Pathways CP-461, Yakult Honsha CPT-11,crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609,DABIS maleate, dacarbazine, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin®, Cell PathwaysExisulind® (sulindac sulphone or CP-246), fenretinide, Merck ResearchLabs Finasteride, Florical, Fujisawa FR-57704, gallium nitrate,gemcitabine, genkwadaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, irinotecan,isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, ketoconazole,Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, AmericanCyanamid L-623, leucovorin, levamisole, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, Monocal, mopidamol, motretinide,Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids, Nilandron;Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom,Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative, Normosang,NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580,octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, retinoids, Encore Pharmaceuticals R-flurbiprofen,Sandostatin; Sapporo Breweries RBS, restrictin-P, retelliptine, retinoicacid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Scherring-PloughSC-57050, Scherring-Plough SC-57068, seienium(selenite andselenomethionine), SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, Sugen SU-101, SugenSU-5416, Sugen SU-6668, sulindac, sulindac sulfone; superoxidedismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, and Zanosar.

Preferred miscellaneous agents that may be used in the present inventioninclude, but are not limited to, those identified in Table No. 6, below.

TABLE No. 6 Miscellaneous agents Common Name/ Compound Trade NameCompany Reference Dosage Flutamide; 2- EUL- Schering 750 mg/d inmethyl-N-(4- EXIN ® Corp 3 8-hr nitro-3- doses. (trifluoro-methyl)phenyl) propanamide Ketocon- U.S. Pat. No. azole 4144346 leucovo-U.S. Pat. No. rin 4148999 irinote- U.S. Pat. No. can 4604463 levamis- GBole 11/20406 megestrol U.S. Pat. No. 4696949 paclita- U.S. Pat. No. xel5641803 Nilutamide Nilandron Hoechst A total 5,5-dimethyl Marion dailydose 3-(4-nitro 3- Roussel of 300 mg (tri- for 30 days fluoromethyl)followed phenyl) 2,4- thereafter imidazolidined by three ione tablets(50 mg each) once a day for a total daily dosage of 150 mg. Vinorel- EP0010458 bine vinblas- tine vincris- tine Octreotide Sandosta- Sandozs.c. or acetate L- tin Pharma- i.v. cysteinamide, ceuticals administra-D- tion phenylalanyl- Acromegaly: L-cysteinyl-L- 50-300 phenylalanyl-mcgm tid. D-tryptophyl- Carcinoid L-lysyl-L- tumors: threonyl- 100-600NSAIDs-(2- mcgm/d hydroxy-1 (mean = 300 (hydroxy- mcgm/d) methyl)Vipomas: propyl)-, 200-300 cyclic- mcgm in disulfide; (R- first two(R*,R*) weeks of acetate salt therapy Streptozocin Zanosar Pharmaciai.v. 1000 Streptozocin & Upjohn mg/M2 of 2-deoxy-2- body (((methylnitrosurface per samino)- week for carbonyl) two weeks. amino)- alpha(andbeta)-D- glucopyranose) topotecan U.S. Pat. No. 5004758 Selenium EP804927 L- ACE ® J. R. selenomethio- Carlson nine Labor- atories calciumcarbonate sulindac Exisuland ® U.S. Pat. No. sulfone 5858694 ursodeoxy-U.S. Pat. No. cholic acid 5843929 Cell Pathways CP-461

Some additional preferred antineoplastic agents include those describedin the individual patents listed in Table No. 7 below, and are herebyindividually incorporated by reference.

TABLE No. 7 Antineoplastic agents EP 0296749 EP 0882734 EP 00253738 GB02/135425 WO 09/832762 EP 0236940 U.S. Pat. No. 5338732 U.S. Pat. No.4418068 U.S. Pat. No. 4692434 U.S. Pat. No. 5464826 U.S. Pat. No.5061793 EP 0702961 EP 0702961 EP 0702962 EP 0095875 EP 0010458 EP0321122 U.S. Pat. No. 5041424 JP 60019790 WO 09/512606 U.S. Pat. No.4,808614 U.S. Pat. No. 4526988 CA 2128644 U.S. Pat. No. 5455270 WO99/25344 WO 96/27014 U.S. Pat. No. 5695966 DE 19547958 WO 95/16693 WO82/03395 U.S. Pat. No. 5789000 U.S. Pat. No. 5902610 EP 189990 U.S. Pat.No. 4500711 FR 24/74032 U.S. Pat. No. 5925699 WO 99/25344 U.S. Pat. No.4537883 U.S. Pat. No. 4808614 U.S. Pat. No. 5464826 U.S. Pat. No.5366734 U.S. Pat. No. 4767628 U.S. Pat. No. 4100274 U.S. Pat. No.4584305 U.S. Pat. No. 4336381 JP 5050383 JP 5050384 JP 5064281 JP51146482 JP 5384981 U.S. Pat. No. 5472949 U.S. Pat. No. 5455270 U.S.Pat. No. 4140704 U.S. Pat. No. 4537883 U.S. Pat. No. 4814470 U.S. Pat.No. 3590028 U.S. Pat. No. 4564675 U.S. Pat. No. 4526988 U.S. Pat. No.4100274 U.S. Pat. No. 4604463 U.S. Pat. No. 4144346 U.S. Pat. No.4749713 U.S. Pat. No. 4148999 GB 11/20406 U.S. Pat. No. 4696949 U.S.Pat. No. 4310666 U.S. Pat. No. 5641803 U.S. Pat. No. 4418068 U.S. Pat.No. 5,004758 EP 0095875 EP 0010458 U.S. Pat. No. 4935437 U.S. Pat. No.4,278689 U.S. Pat. No. 4820738 U.S. Pat. No. 4413141 U.S. Pat. No.5843917 U.S. Pat. No. 5,858694 U.S. Pat. No. 4330559 U.S. Pat. No.5851537 U.S. Pat. No. 4499072 U.S. Pat. No. 5,217886 WO 98/25603 WO98/14188

Table No. 8 provides illustrative examples of median dosages forselected cancer agents that may be used in combination with anantiangiogenic agent. It should be noted that specific dose regimen forthe chemotherapeutic agents below depends upon dosing considerationsbased upon a variety of factors including the type of neoplasia; thestage of the neoplasm; the age, weight, sex, and medical condition ofthe patient; the route of administration; the renal and hepatic functionof the patient; and the particular combination employed.

TABLE No. 8 Median dosages for selected cancer agents. NAME OFCHEMOTHERAPEUTIC AGENT MEDIAN DOSAGE Asparaginase 10,000 units BleomycinSulfate 15 units Carboplatin 50-450 mg. Carmustine 100 mg. Cisplatin10-50 mg. Cladribine 10 mg. Cyclophosphamide 100 mg.-2 gm. (lyophilized)Cyclophosphamide (non- 100 mg.-2 gm. lyophilized) Cytarabine(lyophilized 100 mg.-2 gm. powder) Dacarbazine 100 mg.-200 mg.Dactinomycin 0.5 mg. Daunorubicin 20 mg. Diethylstilbestrol 250 mg.Doxorubicin 10-150 mg. Etidronate 300 mg. Etoposide 100 mg. Floxuridine500 mg. Fludarabine Phosphate 50 mg. Fluorouracil 500 mg.-5 gm.Goserelin 3.6 mg. Granisetron Hydrochloride 1 mg. Idarubicin 5-10 mg.Ifosfamide 1-3 gm. Leucovorin Calcium 50-350 mg. Leuprolide 3.75-7.5rng. Mechlorethamine 10 mg. Medroxyprogesterone 1 gm. Melphalan 50 gm.Methotrexate 20 mg.-1 gm. Mitomycin 5-40 mg. Mitoxantrone 20-30 mg.Ondansetron Hydrochloride 40 mg. Paclitaxel 30 mg. Pamidronate Disodium30-90 mg. Pegaspargase 750 units Plicamycin 2,500 mcgm. Streptozocin 1gm. Thiotepa 15 mg. Teniposide 50 mg. Vinblastine 10 mg. Vincristine 1-5mg. Aldesleukin 22 million units Epoetin Alfa 2,000-10,000 unitsFilgrastim 300-480 mcgm. Immune Globulin 500 mg.-10 gm. InterferonAlpha-2a 3-36 million units Interferon Alpha-2b 3-50 million unitsLevamisole 50 mg. Octreotide 1,000-5,000 mcgm. Sargramostim 250-500mcgm.

The anastrozole used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in U.S. Pat. No.4,935,437. The capecitabine used in the therapeutic combinations of thepresent invention can be prepared in the manner set forth in U.S. Pat.No. 5,472,949. The carboplatin used in the therapeutic combinations ofthe present invention can be prepared in the manner set forth in U.S.Pat. No. 5,455,270. The Cisplatin used in the therapeutic combinationsof the present invention can be prepared in the manner set forth in U.S.Pat. No. 4,140,704. The cyclophoshpamide used in the therapeuticcombinations of the present invention can be prepared in the manner setforth in U.S. Pat. No. 4,537,883. The eflornithine (DFMO) used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 4,413,141. The docetaxel used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 4,814,470. The doxorubicin used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 3,590,028. The etoposide used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 4,564,675. The fluorouricil used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 4,336,381. The gemcitabine used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 4,526,988. The goserelin used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 4,100,274. The irinotecan used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 4,604,463. The ketoconazole usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 4,144,346. The letrozole usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 4,749,713. The leucovorin usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 4,148,999. The levamisole usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in GB 11/20,406. The megestrol used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 4,696,949. The mitoxantrone used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 4,310,666. The paclitaxel used inthe therapeutic combinations of the present invention can be prepared inthe manner set forth in U.S. Pat. No. 5,641,803. The Retinoic acid usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 4,843,096. The tamoxifen usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 4,418,068. The topotecan usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in U.S. Pat. No. 5,004,758. The toremifene usedin the therapeutic combinations of the present invention can be preparedin the manner set forth in EP 00/095,875. The vinorelbine used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in EP 00/010,458. The sulindac sulfone used in thetherapeutic combinations of the present invention can be prepared in themanner set forth in U.S. Pat. No. 5,858,694. The selenium(selenomethionine) used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in EP 08/04,927. Theursodeoxycholic acid used in the therapeutic combinations of the presentinvention can be prepared in the manner set forth in WO 97/34,608.Ursodeoxycholic acid can also be prepared according to the manner setforth in EP 05/99,282. Finally, ursodeoxycholic acid can be preparedaccording to the manner set forth in U.S. Pat. No. 5,843,929.

Still more preferred antineoplastic agents include: anastrozole, calciumcarbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461,cyclophosphamide, docetaxel, doxorubicin, etoposide, Exisulind®,fluorouracil (5-FU), fluoxymestrine, gemcitabine, goserelin, irinotecan,ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone,paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan,toremifene, vinorelbine, vinblastine, vincristine, selenium(selenomethionine), ursodeoxycholic acid, sulindac sulfone andeflornithine (DFMO).

The phrase “taxane” includes a family of diterpene alkaloids all ofwhich contain a particular eight (8) member “taxane” ring structure.Taxanes such as paclitaxel prevent the normal post division breakdown ofmicrotubules which form to pull and separate the newly duplicatedchromosome pairs to opposite poles of the cell prior to cell division.In cancer cells which are rapidly dividing, taxane therapy causes themicrotubules to accumulate which ultimately prevents further division ofthe cancer cell. Taxane therapy also affects other cell processesdependant on microtubules such as cell motility, cell shape andintracellular transport. The major adverse side-effects associated withtaxane therapy can be classified into cardiac effects, neurotoxicity,haematological toxicity, and hypersensitivity reactions. (See Exp. Opin.Thera. Patents (1998) 8(5), hereby incorporated by reference). Specificadverse side-effects include neutropenia, alopecia, bradycardia, cardiacconduction defects, acute hypersensitivity reactions, neuropathy,mucositis, dermatitis, extravascular fluid accumulation, arthralgias,and myalgias. Various treatment regimens have been developed in aneffort to minimize the side effects of taxane therapy, but adverseside-effects remain the limiting factor in taxane therapy.

Taxane derivatives have been found to be useful in treating refractoryovarian carcinoma, urothelial cancer, breast carcinoma, melanoma,non-small-cell lung carcinoma, gastric, and colon carcinomas, squamouscarcinoma of the head and neck, lymphoblastic, myeloblastic leukemia,and carcinoma of the esophagus.

Paclitaxel is typically administered in a 15-420 mg/m² dose over a 6 to24 hour infusion. For renal cell carcinoma, squamous carcinoma of headand neck, carcinoma of esophagus, small and non-small cell lung cancer,and breast cancer, paclitaxel is typically administered as a 250 mg/m²24 hour infusion every 3 weeks. For refractory ovarian cancer paclitaxelis typically dose escalated starting at 110 mg/m². Docetaxel istypically administered in a 60-100 mg/M² i.v. over 1 hour, every threeweeks. It should be noted, however, that specific dose regimen dependsupon dosing considerations based upon a variety of factors including thetype of neoplasia; the stage of the neoplasm; the age, weight, sex, andmedical condition of the patient; the route of administration; the renaland hepatic function of the patient; and the particular agents andcombination employed.

In one embodiment, paclitaxel is used in the present invention incombination with a matrix metalloproteinase inhibitor and withcisplatin, cyclophosphamide, or doxorubicin for the treatment of breastcancer. In another embodiment paciltaxel is used in combination with amatrix metalloproteinase inhibitor, cisplatin or carboplatin, andifosfamide for the treatment of ovarian cancer.

In another embodiment docetaxal is used in the present invention incombination with a matrix metalloproteinase inhibitor and in combinationwith cisplatin, cyclophosphamide, or doxorubicin for the treatment ofovary and breast cancer and for patients with locally advanced ormetastatic breast cancer who have progressed during anthracycline basedtherapy.

The following references listed in Table No. 9 below, herebyindividually incorporated by reference herein, describe various taxanesand taxane derivatives suitable for use in the present invention, andprocesses for their manufacture.

TABLE No. 9 Taxanes and taxane derivatives EP 694539 EP 683232 EP 639577EP 627418 EP 604910 EP 797988 EP 727492 EP 767786 EP 767376 U.S. Pat.No. 5886026 U.S. Pat. No. 5880131 U.S. Pat. No. 5879929 U.S. Pat. No.5871979 U.S. Pat. No. 5869680 U.S. Pat. No. 5871979 U.S. Pat. No.5854278 U.S. Pat. No. 5840930 U.S. Pat. No. 5840748 U.S. Pat. No.5827831 U.S. Pat. No. 5824701 U.S. Pat. No. 5821363 U.S. Pat. No.5821263 U.S. Pat. No. 5811292 U.S. Pat. No. 5808113 U.S. Pat. No.5808102 U.S. Pat. No. 5807888 U.S. Pat. No. 5780653 U.S. Pat. No.5773461 U.S. Pat. No. 5770745 U.S. Pat. No. 5767282 U.S. Pat. No.5763628 U.S. Pat. No. 5760252 U.S. Pat. No. 5760251 U.S. Pat. No.5756776 U.S. Pat. No. 5750737 U.S. Pat. No. 5744592 U.S. Pat. No.5739362 U.S. Pat. No. 5728850 U.S. Pat. No. 5728725 U.S. Pat. No.5723634 U.S. Pat. No. 5721268 U.S. Pat. No. 5717115 U.S. Pat. No.5716981 U.S. Pat. No. 5714513 U.S. Pat. No. 5710287 U.S. Pat. No.5705508 U.S. Pat. No. 5703247 U.S. Pat. No. 5703117 U.S. Pat. No.5700669 U.S. Pat. No. 5693666 U.S. Pat. No. 5688977 U.S. Pat. No.5684175 U.S. Pat. No. 5683715 U.S. Pat. No. 5679807 U.S. Pat. No.5677462 U.S. Pat. No. 5675025 U.S. Pat. No. 5670673 U.S. Pat. No.5654448 U.S. Pat. No. 5654447 U.S. Pat. No. 5646176 U.S. Pat. No.5637732 U.S. Pat. No. 5637484 U.S. Pat. No. 5635531 U.S. Pat. No.5631278 U.S. Pat. No. 5629433 U.S. Pat. No. 5622986 U.S. Pat. No.5618952 U.S. Pat. No. 5616740 U.S. Pat. No. 5616739 U.S. Pat. No.5614645 U.S. Pat. No. 5614549 U.S. Pat. No. 5608102 U.S. Pat. No.5599820 U.S. Pat. No. 5594157 U.S. Pat. No. 5587489 U.S. Pat. No.5580899 U.S. Pat. No. 5574156 U.S. Pat. No. 5567614 U.S. Pat. No.5565478 U.S. Pat. No. 5560872 U.S. Pat. No. 5556878 U.S. Pat. No.5547981 U.S. Pat. No. 5539103 U.S. Pat. No. 5532363 U.S. Pat. No.5530020 U.S. Pat. No. 5508447 U.S. Pat. No. 5489601 U.S. Pat. No.5484809 U.S. Pat. No. 5475011 U.S. Pat. No. 5473055 U.S. Pat. No.5470866 U.S. Pat. No. 5466834 U.S. Pat. No. 5449790 U.S. Pat. No.5442065 U.S. Pat. No. 5440056 U.S. Pat. No. 5430160 U.S. Pat. No.5412116 U.S. Pat. No. 5412092 U.S. Pat. No. 5411984 U.S. Pat. No.5407816 U.S. Pat. No. 5407674 U.S. Pat. No. 5405972 U.S. Pat. No.5399726 U.S. Pat. No. 5395850 U.S. Pat. No. 5384399 U.S. Pat. No.5380916 U.S. Pat. No. 5380751 U.S. Pat. No. 5367086 U.S. Pat. No.5356928 U.S. Pat. No. 5356927 U.S. Pat. No. 5352806 U.S. Pat. No.5350866 U.S. Pat. No. 5344775 U.S. Pat. No. 5338872 U.S. Pat. No.5336785 U.S. Pat. No. 5319112 U.S. Pat. No. 5296506 U.S. Pat. No.5294737 U.S. Pat. No. 5294637 U.S. Pat. No. 5284865 U.S. Pat. No.5284864 U.S. Pat. No. 5283253 U.S. Pat. No. 5279949 U.S. Pat. No.5274137 U.S. Pat. No. 5274124 U.S. Pat. No. 5272171 U.S. Pat. No.5254703 U.S. Pat. No. 5254580 U.S. Pat. No. 5250683 U.S. Pat. No.5243045 U.S. Pat. No. 5229526 U.S. Pat. No. 5227400 U.S. Pat. No.5200534 U.S. Pat. No. 5194635 U.S. Pat. No. 5175,315 U.S. Pat. No.5136060 U.S. Pat. No. 5015744 WO 98/38862 WO 95/24402 WO 93/21173 EP681574 EP 681575 EP 568203 EP 642503 EP 667772 EP 668762 EP 679082 EP681573 EP 688212 EP 690712 EP 690853 EP 710223 EP 534708 EP 534709 EP605638 EP 669918 EP 855909 EP 605638 EP 428376 EP 428376 EP 534707 EP605637 EP 679156 EP 689436 EP 690867 EP 605637 EP 690867 EP 687260 EP690711 EP 400971 EP 690711 EP 400971 EP 690711 EP 884314 EP 568203 EP534706 EP 428376 EP 534707 EP 400971 EP 669918 EP 605637 U.S. Pat. No.5015744 U.S. Pat. No. 5175315 U.S. Pat. No. 5243045 U.S. Pat. No.5283253 U.S. Pat. No. 5250683 U.S. Pat. No. 5254703 U.S. Pat. No.5274124 U.S. Pat. No. 5284864 U.S. Pat. No. 5284865 U.S. Pat. No.5350866 U.S. Pat. No. 5227400 U.S. Pat. No. 5229526 U.S. Pat. No.4876399 U.S. Pat. No. 5136060 U.S. Pat. No. 5336785 U.S. Pat. No.5710287 U.S. Pat. No. 5714513 U.S. Pat. No. 5717115 U.S. Pat. No.5721268 U.S. Pat. No. 5723634 U.S. Pat. No. 5728725 U.S. Pat. No.5728850 U.S. Pat. No. 5739362 U.S. Pat. No. 5760219 U.S. Pat. No.5760252 U.S. Pat. No. 5384399 U.S. Pat. No. 5399726 U.S. Pat. No.5405972 U.S. Pat. No. 5430160 U.S. Pat. No. 5466834 U.S. Pat. No.5489601 U.S. Pat. No. 5532363 U.S. Pat. No. 5539103 U.S. Pat. No.5574156 U.S. Pat. No. 5587489 U.S. Pat. No. 5618952 U.S. Pat. No.5637732 U.S. Pat. No. 5654447 U.S. Pat. No. 4942184 U.S. Pat. No.5059699 U.S. Pat. No. 5157149 U.S. Pat. No. 5202488 U.S. Pat. No.5750736 U.S. Pat. No. 5202488 U.S. Pat. No. 5549830 U.S. Pat. No.5281727 U.S. Pat. No. 5019504 U.S. Pat. No. 4857653 U.S. Pat. No.4924011 U.S. Pat. No. 5733388 U.S. Pat. No. 5696153 WO 93/06093 WO93/06094 WO 94/10996 WO 9/10997 WO 94/11362 WO 94/15599 WO 94/15929 WO94/17050 WO 94/17051 WO 94/17052 WO 94/20088 WO 94/20485 WO 94/21250 WO94/21251 WO 94/21252 WO 94/21623 WO 94/21651 WO 95/03265 WO 97/09979 WO97/42181 WO 99/08986 WO 99/09021 WO 93/06079 U.S. Pat. No. 5202448 U.S.Pat. No. 5019504 U.S. Pat. No. 4657653 U.S. Pat. No. 4924011 WO 97/15571WO 96/38138 U.S. Pat. No. 5489589 EP 781778 WO 96/11683 EP 639577 EP747385 U.S. Pat. No. 5422364 WO 95/11020 EP 747372 WO 96/36622 U.S. Pat.No. 5599820 WO 97/10234 WO 96/21658 WO 97/23472 U.S. Pat. No. 5550261 WO95/20582 WO 97/28156 WO 96/14309 WO 97/32587 WO 96/28435 WO 96/03394 WO95/25728 WO 94/29288 WO 96/00724 WO 95/02400 EP 694539 WO 95/24402 WO93/10121 WO 97/19086 WO 97/20835 WO 96/14745 WO 96/36335

U.S. Pat. No. 5,019,504 describes the isolation of paclitaxel andrelated alkaloids from culture grown Taxus brevifolia cells.

U.S. Pat. No. 5,675,025 describes methods for synthesis of Taxol®,Taxol® analogues and intermediates from baccatin III.

U.S. Pat. No. 5,688,977 describes the synthesis of Docetaxel from10-deacetyl baccatin III.

U.S. Pat. No. 5,202,488 describes the conversion of partially purifiedtaxane mixture to baccatin III.

U.S. Pat. No. 5,869,680 describes the process of preparing taxanederivatives.

U.S. Pat. No. 5,856,532 describes the process of the production ofTaxol®.

U.S. Pat. No. 5,750,737 describes the method for paclitaxel synthesis.

U.S. Pat. No. 6,688,977 describes methods for docetaxel synthesis.

U.S. Pat. No. 5,677,462 describes the process of preparing taxanederivatives.

U.S. Pat. No. 5,594,157 describes the process of making Taxol®derivatives.

Some preferred taxanes and taxane derivatives are described in thepatents listed in Table No. 10 below, and are hereby individuallyincorporated by reference herein.

TABLE No. 10 Some preferred taxanes and taxane derivatives U.S. Pat. No.5015744 U.S. Pat. No. 5136060 U.S. Pat. No. 5175315 U.S. Pat. No.5200534 U.S. Pat. No. 5194635 U.S. Pat. No. 5227400 U.S. Pat. No.4924012 U.S. Pat. No. 5641803 U.S. Pat. No. 5059699 U.S. Pat. No.5157049 U.S. Pat. No. 4942184 U.S. Pat. No. 4960790 U.S. Pat. No.5202488 U.S. Pat. No. 5675025 U.S. Pat. No. 5688977 U.S. Pat. No.5750736 U.S. Pat. No. 5684175 U.S. Pat. No. 5019504 U.S. Pat. No.4814470 WO 95/01969

The phrase “retinoid” includes compounds which are natural and syntheticanalogues of retinol (Vitamin A). The retinoids bind to one or moreretinoic acid receptors to initiate diverse processes such asreproduction, development, bone formation, cellular proliferation anddifferentiation, apoptosis, hematopoiesis, immune function and vision.Retinoids are required to maintain normal differentiation andproliferation of almost all cells and have been shown toreverse/suppress carcinogenesis in a variety of in vitro and in vivoexperimental models of cancer, see (Moon et al., Ch. 14 Retinoids andcancer. In The Retinoids, Vol. 2. Academic Press, Inc. 1984). Also seeRoberts et al. Cellular biology and biochemistry of the retinoids. InThe Retinoids, Vol. 2. Academic Press, Inc. 1984, hereby incorporated byreference), which also shows that vesanoid (tretinoid trans retinoicacid) is indicated for induction of remission in patients with acutepromyelocytic leukemia (APL).

A synthetic description of retinoid compounds, hereby incorporated byreference, is described in: Dawson M I and Hobbs P D. The syntheticchemistry of retinoids: in The retinoids, 2^(nd) edition. M B Sporn, A BRoberts, and D S Goodman (eds). New York: Raven Press, 1994, pp 5-178.

Lingen et al. describe the use of retinoic acid and interferon alphaagainst head and neck squamous cell carcinoma (Lingen, M W et al.,Retinoic acid and interferon alpha act synergistically as antiangiogenicand antitumor agents against human head and neck squamous cellcarcinoma. Cancer Research 58 (23) 5551-5558 (1998), hereby incorporatedby reference).

Iurlaro et al. describe the use of beta interferon and 13-cis retinoicacid to inhibit angiogenesis. (Iurlaro, M et al., Beta interferoninhibits HIV-1 Tat-induced angiogenesis: synergism with 13-cis retinoicacid. European Journal of Cancer 34 (4) 570-576 (1998), herebyincorporated by reference).

Majewski et al. describe Vitamin D3 and retinoids in the inhibition oftumor cell-induced angiogenesis. (Majewski, S et al., Vitamin D3 is apotent inhibitor of tumor cell-induced angiogenesis. J. Invest.Dermatology. Symposium Proceedings, 1 (1), 97-101 (1996), herebyincorporated by reference.

Majewski et al. describe the role of retinoids and other factors intumor angiogenesis. Majewski, S et al., Role of cytokines, retinoids andother factors in tumor angiogenesis. Central-European journal ofImmunology 21 (4) 281-289 (1996), hereby incorporated by reference).

Bollag describes retinoids and alpha-interferon in the prevention andtreatment of neoplastic disease. (Bollag W. Retinoids andalpha-interferon in the prevention and treatment of preneoplastic andneoplastic diseases. Chemotherapie Journal, (Suppl) 5 (10) 55-64 (1996),hereby incorporated by reference.

Bigg, H F et al. describe all-trans retinoic acid with basic fibroblastgrowth factor and epidermal growth factor to stimulate tissue inhibitorof metalloproteinases from fibroblasts. (Bigg, H F et al.,All-trans-retoic acid interacts synergystically with basic fibroblastgrowth factor and epidermal growth factor to stimulate the production oftissue inhibitor of metalloproteinases from fibroblasts. Arch. Biochem.Biophys. 319 (1) 74-83 (1995), hereby incorporated by reference).

Nonlimiting examples of retinoids that may be used in the presentinvention are identified in Table No. 11 below.

TABLE No. 11 Retinoids Common Name/ Compound Trade Name CompanyReference Dosage CD-271 Adapaline EP 199636 Tretinoin Vesanoid Roche 45trans Holdings mg/M²/day retinoic as two acid evenly divided doses untilcomplete remission 2,4,6,8- etretinate Roche US .25-1.5 Nonatetra-isoetret- Holdings 4215215 mg/kg/day enoic acid, in; Ro-10- 9-(4- 9359;Ro- methoxy- 13-7652; 2,3,6- Tegison; trimethyl- Tigason phenyl)-3,7-dimethyl- ethyl ester, (all-E)- Retinoic isotre- Roche US .5 to 2 acid,13- tinoin Holdings 4843096 mg/kg/day cis- Accutane; Isotrex; Ro-4-3780;Roaccutan; Roaccutane Roche Ro- Roche 40-0655 Holdings Roche Ro- Roche25-6760 Holdings Roche Ro- Roche 25-9022 Holdings Roche Ro- Roche25-9716 Holdings Benzoic TAC-101 Taiho acid, 4- Pharma- [[3,5- ceuticalbis(tri- methyl- silyl)- benzoyl] amino]- Retinamide, fenretinide 50-400N-(4- 4-HPR; mg/kg/day hydroxy- HPR; McN- phenyl)- R-1967 (2E,4E,6E)-LGD-1550 Ligand 20 7-(3,5-Di- ALRT-1550; Pharma- microg/m2/ tert-ALRT-550; ceuticas; day to butylphenyl) LG-1550 Allergan 400 -3- USAmicrog/m2/ methylocta- day 2,4,6- adminis- trienoic tered as a acidsingle daily oral dose Molecular US Design 4885311 MDI-101 Molecular USDesign 4677120 MDI-403 Benzoic bexarotene WO acid, 4-(1- LG-1064;94/15901 (5,6,7,8- LG-1069; tetrahydro- LGD-1069; 3,5,5,8,8- Targretin;pentamethyl Targretin -2- Oral; naphtha- Targretin lenyl) Topicalethenyl)- Gel Benzoic bexarotene, R P acid, 4-(1- soft gel, Scherer(5,6,7,8- bexarotene, tetrahydro- Ligand; 3,5,8,8- bexaroten pentamethyl-2- naphthalenyl) ethenyl)- (2E,4E)-3- WO methyl-5- 96/05165 [3-(5,5,8,8 tetramethyl -5,6,7,8- tetrahydro- naphthalen- 2-yl)- thiopen-2-yl]-penta- 2,4-dienoic acid SR-11262 Hoffmann F -La Roche Ltd BMS-Bristol EP 476682 181162 Myers Squibb N-(4- IIT Cancer hydroxy- ResearchResearch phenyl) Institute 39, retinamide 1339-1346 (1979) AGN- AllerganWO 193174 USA 96/33716

The following individual patent references listed in Table No. 12 below,hereby individually incorporated by reference, describe various retinoidand retinoid derivatives suitable for use in the present inventiondescribed herein, and processes for their manufacture.

TABLE No. 12 Retinoids U.S. Pat. No. 4215215 U.S. Pat. No. 4885311 U.S.Pat. No. 4677120 U.S. Pat. No. 4105681 U.S. Pat. No. 5260059 U.S. Pat.No. 4503035 U.S. Pat. No. 5827836 U.S. Pat. No. 3878202 U.S. Pat. No.4843096 WO 96/05165 WO 97/34869 WO 97/49704 U.S. Pat. No. 5547947 EP552624 EP 728742 EP 331983 EP 19/9636 WO 96/33716 WO 97/24116 WO97/09297 WO 98/36742 WO 97/25969 WO 96/11686 WO 94/15901 WO 97/24116 CH61/6134 DE 2854354 EP 579915 EP 476682

Some preferred retinoids include Accutane; Adapalene; AllerganAGN-193174; Allergan AGN-193676; Allergan AGN-193836; AllerganAGN-193109; Aronex AR-623; BMS-181162; Galderma CD-437; Eisai ER-34617;Etrinate; Fenretinide; Ligand LGD-1550; lexacalcitol; MaxiaPharmaceuticals MX-781; mofarotene; Molecular Design MDI-101; MolecularDesign MDI-301; Molecular Design MDI-403; Motretinide; Eisai4-(2-[5-(4-methyl-7-ethylbenzofuran-2-yl)pyrrolyl])benzoic acid; Johnson& JohnsonN-[4-[2-thyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzothiazolamine;Soriatane; Roche SR-11262; Tocoretinate; Advanced Polymer Systemstrans-retinoic acid; UAB Research Foundation UAB-8; Tazorac; TopiCare;Taiho TAC-101; and Vesanoid.

cGMP phosphodiesterase inhibitors, including Sulindac sulfone(Exisuland®) and CP-461 for example, are apoptosis inducers and do notinhibit the cyclooxygenase pathways. cGMP phosphodiesterase inhibitorsincrease apoptosis in tumor cells without arresting the normal cycle ofcell division or altering the cell's expression of the p53 gene.

Ornithine decarboxylase is a key enzyme in the polyamine synthesispathway that is elevated in most tumors and premalignant lesions.Induction of cell growth and proliferation is associated with dramaticincreases in ornithine decarboxylase activity and subsequent polyaminesynthesis. Further, blocking the formation of polyamines slows orarrests growth in transformed cells. Consequently, polyamines arethought to play a role in tumor growth. Difluoromethylornithine (DFMO)is a potent inhibitor of ornithine decarboxylase that has been shown toinhibit carcinogen-induced cancer development in a variety of rodentmodels (Meyskens et al. Development of Difluoromethylornithine (DFMO) asa chemoprevention agent. Clin. Cancer Res. 1999 May, 5(%):945-951,hereby incorporated by reference, herein). DFMO is also known as2-difluoromethyl-2,5-diaminopentanoic acid, or2-difluoromethyl-2,5-diaminovaleric acid, or a-(difluoromethyl)ornithine; DFMO is marketed under the tradename Elfornithine®.Therefore, the use of DFMO in combination with COX-2 inhibitors iscontemplated to treat or prevent cancer, including but not limited tocolon cancer or colonic polyps.

Populations with high levels of dietary calcium have been reported to beprotected from colon cancer. In vivo, calcium carbonate has been shownto inhibit colon cancer via a mechanism of action independent from COX-2inhibition. Further, calcium carbonate is well tolerated. A combinationtherapy consisting of calcium carbonate and a selective COX-2 inhibitoris contemplated to treat or prevent cancer, including but not limited tocolon cancer or colonic polyps.

Several studies have focused attention on bile acids as a potentialmediator of the dietary influence on colorectal cancer risk. Bile acidsare important detergents for fat solubilization and digestion in theproximal intestine. Specific transprot processes in the apical domain ofthe terminal ileal enterocyte and basolateral domain of the hepatocyteaccount for the efficient conservation in the enterohepatic circulation.Only a small fraction of bile acids enter the colon; however,perturbations of the cycling rate of bile acids by diet (e.g. fat) orsurgery may increase the fecal bile load and perhaps account for theassociated increased risk of colon cancer. (Hill M J, Bile flow andcolon cancer. 238 Mutation Review, 313 (1990). Ursodeoxycholate (URSO),the hydrophilic 7-beta epimer of chenodeoxycholate, is non cytotoxic ina variety of cell model systems including colonic epithelia. URSO isalso virtually free of side effects. URSO, at doses of 15 mg/kg/day usedprimarily in biliary cirrhosis trials were extremely well tolerated andwithout toxicity. (Pourpon et al., A multicenter, controlled trial ofursodiol for the treatment of primary biliary cirrhosis. 324 New Engl.J. Med. 1548 (1991)). While the precise mechanism of URSO action isunknown, beneficial effects of URSO therapy are related to theenrichment of the hepatic bile acid pool with this hydrophilic bileacid. It has thus been hypothesized that bile acids more hydrophilicthan URSO will have even greater beneficial effects than URSO. Forexample, tauroursodeoxycholate (TURSO) the taurine conjugate of URSO.Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit theneoplastic transformation of colorectal epithelium. The likely mechanismto explain this chemopreventive effect is inhibition of prostaglandinsynthesis. NSAIDs inhibit cyclooxygenase, the enzyme that convertsarachidonic acid to prostaglandins and thromboxanes. However, thepotential chemopreventive benefits of NSAIDs such as sulindac ormesalamine are tempered by their well known toxicities and moderatelyhigh risk of intolerance. Abdominal pain, dispepsia, nausea, diarrhea,constipation, rash, dizziness, or headaches have been reported in up to9% of patients. The elderly appear to be particularly vulnerable as theincidence of NSAID-induced gastroduodenal ulcer disease, includinggastrointestinal bleeding, is higher in those over the age of 60; thisis also the age group most likely to develop colon cancer, and thereforemost likely to benefit from chemoprevention. The gastrointestinal sideeffects associated with NSAID use result from the inhibition ofcyclooxygenase-1, an enzyme responsible for maintenance of the gastricmucosa. Therefore, the use of COX-2 inhibitors in combination with URSOis contemplated to treat or prevent cancer, including but not limited tocolon cancer or colonic polyps; it is contemplated that this treatmentwill result in lower gastrointestinal side effects than the combinationof standard NSAIDs and URSO.

An additional class of antineoplastic agents that may be used in thepresent invention include nonsteroidal antiinflammatory drugs (NSAIDs).NSAIDs have been found to prevent the production of prostaglandins byinhibiting enzymes in the human arachidonic acid/prostaglandin pathway,including the enzyme cyclooxygenase (COX). However, for the purposes ofthe present invention the definition of an NSAID does not include the“cyclooxygenase-2 inhibitors” described herein. Thus the phrase“nonsteroidal antiinflammatory drug” or “NSAID” includes agents thatspecifically inhibit cyclooxygenase-1, without significant inhibition ofcyclooxygenase-2; or inhibit cyclooxygenase-1 and cyclooxygenase-2 atsubstantially the same potency; or inhibit neither cyclooxygenase-1 orcyclooxygenase-2. The potency and selectivity for the enzymecyclooxygenase-1 and cyclooxygenase-2 can be determined by assays wellknown in the art, see for example, Cromlish and Kennedy, BiochemicalPharmacology, Vol. 52, pp 1777-1785, 1996.

Examples of NSAIDs that can be used in the combinations of the presentinvention include sulindac, indomethacin, naproxen, diclofenac,tolectin, fenoprofen, phenylbutazone, piroxicam, ibuprofen, ketophen,mefenamic acid, tolmetin, flufenamic acid, nimesulide, niflumic acid,piroxicam, tenoxicam, phenylbutazone, fenclofenac, flurbiprofen,ketoprofen, fenoprofen, acetaminophen, salicylate and aspirin.

The term “clinical tumor” includes neoplasms that are identifiablethrough clinical screening or diagnostic procedures including, but notlimited to, palpation, biopsy, cell proliferation index, endoscopy,mammagraphy, digital mammography, ultrasonography, computed tomagraphy(CT), magnetic resonance imaging (MRI), positron emmission tomaagraphy(PET), radiography, radionuclide evaluation, CT- or MRI-guidedaspiration cytology, and imaging-guided needle biopsy, among others.Such diagnostic techniques are well known to those skilled in the artand are described in Cancer Medicine 4^(th) Edition, Volume One. J. F.Holland, R. C. Bast, D. L. Morton, E. Frei III, D. W. Kufe, and R. R.Weichselbaum (Editors). Williams & Wilkins, Baltimore (1997).

The term “tumor marker” or “tumor biomarker” encompasses a wide varietyof molecules with divergent characteristics that appear in body fluidsor tissue in association with a clinical tumor and also includestumor-associated chromosomal changes. Tumor markers fall primarily intothree categories: molecular or cellular markers, chromosomal markers,and serological or serum markers. Molecular and chromosomal markerscomplement standard parameters used to describe a tumor (i.e.histopathology, grade, tumor size) and are used primarily in refiningdisease diagnosis and prognosis after clinical manifestation. Serummarkers can often be measured many months before clinical tumordetection and are thus useful as an early diagnostic test, in patientmonitoring, and in therapy evaluation.

Molecular Tumor Markers

Molecular markers of cancer are products of cancer cells or molecularchanges that take place in cells because of activation of cell divisionor inhibition of apoptosis. Expression of these markers can predict acell's malignant potential. Because cellular markers are not secreted,tumor tissue samples are generally required for their detection.Non-limiting examples of molecular tumor markers that can be used in thepresent invention are listed in Table No. 1, below.

TABLE 1 Non-limiting Examples of Molecular Tumor Markers Tumor MarkerBreast p53 Breast, ErbB-2/Her-2 Ovarian Breast S phase and ploidy BreastpS2 Breast MDR2 Breast urokinase plasminogen activator Breast, mycfamily Colon, Lung

Chromosomal Tumor Markers

Somatic mutations and chromosomal aberrations have been associated witha variety of tumors. Since the identification of the PhiladelphiaChromosome by Nowel and Hungerford, a wide effort to identifytumor-specific chromosomal alterations has ensued. Chromosomal cancermarkers, like cellular markers, are can be used in the diagnosis andprognosis of cancer. In addition to the diagnostic and prognosticimplications of chromosomal alterations, it is hypothesized thatgerm-line mutations can be used to predict the likelihood that aparticular person will develop a given type of tumor. Non-limitingexamples of chromosomal tumor markers that can be used in the presentinvention are listed in Table No. 2, below.

TABLE 2 Non-limiting Examples of Chromosomal Tumor Markers Tumor MarkerBreast 1p36 loss Breast 6q24-27 loss Breast 11q22-23 loss Breast 11q13amplification Breast TP53 mutation Colon Gain of chromosome 13 ColonDeletion of short arm of chromosome 1 Lung Loss of 3p Lung Loss of 13qLung Loss of 17p Lung Loss of 9p

Serological Tumor Markers

Serum markers including soluble antigens, enzymes and hormones comprisea third category of tumor markers. Monitoring serum tumor markerconcentrations during therapy provides an early indication of tumorrecurrence and of therapy efficacy. Serum markers are advantageous forpatient surveillance compared to chromosomal and cellular markersbecause serum samples are more easily obtainable than tissue samples,and because serum assays can be performed serially and more rapidly.Serum tumor markers can be used to determine appropriate therapeuticdoses within individual patients. For example, the efficacy of acombination regimen consisting of chemotherapeutic and antiangiogenicagents can be measured by monitoring the relevant serum cancer markerlevels. Moreover, an efficacious therapy dose can be achieved bymodulating the therapeutic dose so as to keep the particular serum tumormarker concentration stable or within the reference range, which mayvary depending upon the indication. The amount of therapy can then bemodulated specifically for each patient so as to minimize side effectswhile still maintaining stable, reference range tumor marker levels.Table No. 3 provides non-limiting examples of serological tumor markersthat can be used in the present invention.

TABLE 3 Non-limiting Examples of Serum Tumor Markers Cancer Type MarkerGerm Cell Tumors a-fetoprotein (AFP) Germ Cell Tumors human chorionicgonadotrophin (hCG) Germ Cell Tumors placental alkaline phosphatase(PLAP) Germ Cell Tumors lactate dehydrogenase (LDH) Prostate prostatespecific antigen (PSA) Breast carcinoembryonic antigen (CEA) BreastMUC-1 antigen (CA15-3) Breast tissue polypeptide antigen (TPA) Breasttissue polypeptide specific antigen (TPS) Breast CYFRA 21.1 Breastsoluble erb-B-2 Ovarian CA125 Ovarian OVX1 Ovarian cancer antigen CA72-4Ovarian TPA Ovarian TPS Gastrointestinal CD44v6 Gastrointestinal CEAGastrointestinal cancer antigen CA19-9 Gastrointestinal NCC-ST-439antigen (Dukes C) Gastrointestinal cancer antigen CA242 Gastrointestinalsoluble erb-B-2 Gastrointestinal cancer antigen CA195 GastrointestinalTPA Gastrointestinal YKL-40 Gastrointestinal TPS Esophageal CYFRA 21-1Esophageal TPA Esophageal TPS Esophageal cancer antigen CA19-9 GastricCancer CEA Gastric Cancer cancer antigen CA19-9 Gastric Cancer cancerantigen CA72-4 Lung neruon specific enolase (NSE) Lung CEA \Lung CYFRA21-1 Lung cancer antigen CA 125 Lung TPA Lung squamous cell carcinomaantigen (SCC) Pancreatic cancer ca19-9 Pancreatic cancer ca50 Pancreaticcancer ca119 Pancreatic cancer ca125 Pancreatic cancer CEA Pancreaticcancer Renal Cancer CD44v6 Renal Cancer E-cadherin Renal Cancer PCNA(proliferating cell nuclear antigen)

EXAMPLES

Germ Cell Cancers

Non-limiting examples of tumor markers useful in the present inventionfor the detection of germ cell cancers include, but are not limited to,a-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and its betasubunit (hCGb), lactate dehydrogenase (LDH), and placental alkalinephosphatase (PLAP).

AFP has an upper reference limit of approximately −10 kU/L after thefirst year of life and may be elevated in germ cell tumors,hepatocellular carcinoma and also in gastric, colon, biliary, pancreaticand lung cancers. AFP serum half life is approximately five days afterorchidectomy. According to EGTM recommendations, AFP serum levels lessthan 1,000 kU/L correlate with a good prognosis, AFP levels between1,000 and 10,000 kU/L, inclusive, correlate with intermediate prognosis,and AFP levels greater than 10,000 U/L correlate with a poor prognosis.

HCG is synthesized in the placenta and is also produced by malignantcells. Serum hCG concentrations may be increased in pancreaticadenocarcinomas, islet cell tumors, tumors of the small and large bowel,hepatoma, stomach, lung, ovaries, breast and kidney. Because some tumorsonly hCGb, measurement of both hCG and hCGb is recommended. Normally,serum hCG in men and pre-menopausal women is as high as −5 U/L whilepost-menopausal women have levels up to −10 U/L. Serum half life of hCGranges from 16-24 hours. According to the EGTM, hCG serum levels under5000 U/L correlate with a good prognosis, levels between 5000 and 50000U/L, inclusively correlate with an intermediate prognosis, and hCG serumlevels greater than 50000 U/L correlate with a poor prognosis. Further,normal hCG half lives correlate with good prognosis while prolonged halflives correlate with poor prognosis.

LDH is an enzyme expressed in cardiac and skeletal muscle as well as inother organs. The LDH-1 isoenzyme is most commonly found in testiculargerm cell tumors but can also occur in a variety of benign conditionssuch as skeletal muscle disease and myocardial infarction. Total LDH isused to measure independent prognostic value in patients with advancedgerm cell tumors. LDH levels less than 1.5× the reference range areassociated with a good prognosis, levels between 1.5 and 10× thereference range, inclusive, are associated with an intermediateprognosis, and levels more than 10× the reference range are associatedwith a poor prognosis.

PLAP is a enzyme of alkaline phosphatase normally expressed by placentalsyncytiotrophoblasts. Elevated serum concentrations of PLAP are found inseminomas, non-seminomatous tumors, and ovarian tumors, and may alsoprovide a marker for testicular tumors. PLAP has a normal half lifeafter surgical resection of between 0.6 and 2.8 days.

Prostate Cancer

A nonlimiting example of a tumor marker useful in the present inventionfor the detection of prostate cancer is prostate specific antigen (PSA).PSA is a glycoprotein that is almost exclusively produced in theprostate. In human serum, uncomplexed f-PSA and a complex of f-PSA witha1-anthichymotrypsin make up total PSA (t-PSA). T-PSA is useful indetermining prognosis in patients that are not currently undergoinganti-androgen treatment. Rising t-PSA levels via serial measurementindicate the presence of residual disease.

Breast Cancer

Non-limiting examples of serum tumor markers useful in the presentinvention for the detection of breast cancer include, but is not limitedto carcinoembryonic antigen (CEA) and MUC-1 (CA 15.3). Serum CEA andCA15.3 levels are elevated in patients with node involvement compared topatients without node involvement, and in patients with larger tumorscompared to smaller tumors. Normal range cutoff points (upper limit) are5-10 mg/L for CEA and 35-60 u/ml for CA15.3. Additional specificity(99.3%) is gained by confirming serum levels with two serial increasesof more than 15%.

Ovarian Cancer

A non-limiting example of a tumor marker useful in the present inventionfor the detection of ovarian cancer is CA125. Normally, women have serumCA125 levels between 0-35 kU/L; 99% of post-menopausal women have levelsbelow 20 kU/L. Serum concentration of CA125 after chemotherapy is astrong predictor of outcome as elevated CA125 levels are found inroughly 80% of all patients with epithelial ovarian cancer. Further,prolonged CA125 half-life or a less than 7-fold decrease during earlytreatment is also a predictor of poor disease prognosis.

Gastrointestinal Cancers

A non-limiting example of a tumor marker useful in the present inventionfor the detection of colon cancer is carcinoembryonicantigen (CEA). CEAis a glycoprotein produced during embryonal and fetal development andhas a high sensitivity for advanced carcinomas including those of thecolon, breast, stomach and lung. High pre- or postoperativeconcentrations (>2.5 ng/ml) of CEA are associated with worse prognosisthan are low concentrations. Further, some studies in the literaturereport that slow rising CEA levels indicates local recurrence whilerapidly increasing levels suggests hepatic metastasis.

Lung Cancer

Examples of serum markers useful in the present invention to monitorlung cancer therapy include, but are not limited to, CEA, cytokeratin 19fragments (CYFRA 21-1), and Neuron Specific Enolase (NSE).

NSE is a glycolytic isoenzyme of enolase produced in central andperipheral neurons and malignant tumors of neuroectodermal origin. Atdiagnosis, NSE concentrations greater than 25 ng/mL are suggestive ofmalignancy and lung cancer while concentrations greater than 100 ng/mLare suggestive of small cell lung cancer.

CYFRA 21-1 is a tumor marker test which uses two specific monoclonalantibodies against a cytokeratin 19 fragment. At diagnosis, CYFRA 21-1concentrations greater than 10 ng/mL are suggestive of malignancy whileconcentrations greater than 30 ng/mL are suggestive of lung cancer.

Accordingly, dosing of the matrix metalloproteinase inhibitor andantineoplastic agent may be determined and adjusted based on measurementof tumor markers in body fluids or tissues, particularly based on tumormarkers in serum. For example, a decrease in serum marker level relativeto baseline serum marker prior to administration of the matrixmetalloproteinase inhibitor and antineoplastic agent indicates adecrease in cancer-associated changes and provides a correlation withinhibition of the cancer. In one embodiment, therefore, the method ofthe present invention comprises administering the matrixmetalloproteinase inhibitor and antineoplastic agent at doses that incombination result in a decrease in one or more tumor markers,particularly a decrease in one or more serum tumor markers, in themammal relative to baseline tumor marker levels.

Similarly, decreasing tumor marker concentrations or serum half livesafter administration of the combination indicates a good prognosis,while tumor marker concentrations which decline slowly and do not reachthe normal reference range predict residual tumor and poor prognosis.Further, during follow-up therapy, increases in tumor markerconcentration predicts recurrent disease many months before clinicalmanifestation.

In addition to the above examples, Table No. 4, below, lists severalreferences, hereby individually incorporated by reference herein, thatdescribe tumor markers and their use in detecting and monitoring tumorgrowth and progression.

TABLE 4 Tumor marker references. European Group on Tumor MarkersPublications Committee. Consensus Recommendations. Anticancer Research19: 2785-2820 (1999) Human Cytogenetic Cancer Markers. Sandra R. Wolmanand Stewart Sell (eds.). Totowa, New Jersey: Humana Press. 1997 CellularMarkers of Cancer. Carleton Garrett and Stewart Sell (eds.). Totowa, NewJersey: Human Press. 1995

Also included in the combination of the invention are the isomericforms, prodrugs and tautomers of the described compounds and thepharmaceutically-acceptable salts thereof. Illustrative pharmaceuticallyacceptable salts are prepared from formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic,2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic,b-hydroxybutyric, galactaric and galacturonic acids.

Suitable pharmaceutically-acceptable base addition salts of compounds ofthe present invention include metallic ion salts and organic ion salts.More preferred metallic ion salts include, but are not limited toappropriate alkali metal (group Ia) salts, alkaline earth metal (groupIa) salts and other physiological acceptable metal ions. Such salts canbe made from the ions of aluminum, calcium, lithium, magnesium,potassium, sodium and zinc. Preferred organic salts can be made fromtertiary amines and quaternary ammonium salts, including in part,trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. All of the above salts can be preparedby those skilled in the art by conventional means from the correspondingcompound of the present invention.

Administration Regimen

Any effective treatment regimen can be utilized and readily determinedand repeated as necessary to effect treatment. In clinical practice, thecompositions containing an MMP inhibitor alone or in combination withother therapeutic agents are administered in specific cycles until aresponse is obtained.

For patients who initially present without advanced or metastaticcancer, an MMP inhibitor in combination with another antiangiogenicagent or one or more anticancer agents may be used as an immediateinitial therapy prior to surgery, chemotherapy, or radiation therapy,and as a continuous post-treatment therapy in patients at risk forrecurrence or metastasis (for example, in adenocarcinoma of theprostate, risk for metastasis is based upon high PSA, high Gleason'sscore, locally extensive disease, and/or pathological evidence of tumorinvasion in the surgical specimen). The goal in these patients is toinhibit the growth of potentially metastatic cells from the primarytumor during surgery or radiotherapy and inhibit the growth of tumorcells from undetectable residual primary tumor.

For patients who initially present with advanced or metastatic cancer,an MMP inhibitor in combination with another MMP inhibitor or one ormore anticancer agents of the present invention is used as a continuoussupplement to, or possible replacement for hormonal ablation. The goalin these patients is to slow or prevent tumor cell growth from both theuntreated primary tumor and from the existing metastatic lesions.

In addition, the invention may be particularly efficacious duringpost-surgical recovery, where the present compositions and methods maybe particularly effective in lessening the chances of recurrence of atumor engendered by shed cells that cannot be removed by surgicalintervention.

Combinations with Other Treatments

MMP inhibitors may be used in conjunction with other treatmentmodalities, including, but not limited to surgery and radiation,hormonal therapy, chemotherapy, immunotherapy, antiangiogenic therapyand cryotherapy. The present invention may be used in conjunction withany current or future therapy.

The following discussion highlights some agents in this respect, whichare illustrative, not limitative. A wide variety of other effectiveagents also may be used.

Surgery and Radiation

In general, surgery and radiation therapy are employed as potentiallycurative therapies for patients under 70 years of age who present withclinically localized disease and are expected to live at least 10 years.

For example, approximately 70% of newly diagnosed prostate cancerpatients fall into this category. Approximately 90% of these patients(65% of total patients) undergo surgery, while approximately 10% ofthese patients (7% of total patients) undergo radiation therapy.Histopathological examination of surgical specimens reveals thatapproximately 63% of patients undergoing surgery (40% of total patients)have locally extensive tumors or regional (lymph node) metastasis thatwas undetected at initial diagnosis. These patients are at asignificantly greater risk of recurrence. Approximately 40% of thesepatients will actually develop recurrence within five years aftersurgery. Results after radiation are even less encouraging.Approximately 80% of patients who have undergone radiation as theirprimary therapy have disease persistence or develop recurrence ormetastasis within five years after treatment. Currently, most of thesesurgical and radiotherapy patients generally do not receive anyimmediate follow-up therapy. Rather, for example, they are monitoredfrequently for elevated Prostate Specific Antigen (“PSA”), which is theprimary indicator of recurrence or metastasis prostate cancer.

Thus, there is considerable opportunity to use the present invention inconjunction with surgical intervention.

Hormonal Therapy

Hormonal ablation is the most effective palliative treatment for the 10%of patients presenting with metastatic prostate cancer at initialdiagnosis. Hormonal ablation by medication and/or orchiectomy is used toblock hormones that support the further growth and metastasis ofprostate cancer. With time, both the primary and metastatic tumors ofvirtually all of these patients become hormone-independent and resistantto therapy. Approximately 50% of patients presenting with metastaticdisease die within three years after initial diagnosis, and 75% of suchpatients die within five years after diagnosis. Continuoussupplementation with NAALADase inhibitor based drugs are used to preventor reverse this potentially metastasis-permissive state.

Among hormones which may be used in combination with the presentinventive compounds, diethylstilbestrol (DES), leuprolide, flutamide,cyproterone acetate, ketoconazole and amino glutethimide are preferred.

Immunotherapy

The MMP inhibitors may also be used in combination with monoclonalantibodies in treating cancer. For example monoclonal antibodies may beused in treating prostate cancer. A specific example of such an antibodyincludes cell membrane-specific anti-prostate antibody.

The present invention may also be used with immunotherapies based onpolyclonal or monoclonal antibody-derived reagents, for instance.Monoclonal antibody-based reagents are most preferred in this regard.Such reagents are well known to persons of ordinary skill in the art.Radiolabelled monoclonal antibodies for cancer therapy, such as therecently approved use of monoclonal antibody conjugated withstrontium-89, also are well known to persons of ordinary skill in theart.

Antiangiogenic Therapy

The MMP inhibitors may also be used in combination with otherantiangiogenic agents in treating cancer. Antiangiogenic agents includebut are not limited to COX-2 inhibitors, integrin antagonists,angiostatin, endostatin, thrombospondin-1, and interferon alpha.Examples of preferred antiangiogenic agents include, but are not limitedto vitaxin, celecoxib, rofecoxib, JTE-522, EMD-121974, and D-2163(BMS-275291).

Cryotherapy

Cryotherapy recently has been applied to the treatment of some cancers.Methods and compositions of the present invention also could be used inconjunction with an effective therapy of this type.

All of the various cell types of the body can be transformed into benignor malignant neoplasia or tumor cells and are contemplated as objects ofthe invention. A “benign” tumor cell denotes the non-invasive andnon-metastasized state of a neoplasm. In man the most frequent neoplasiasite is lung, followed by colorectal, breast, prostate, bladder,pancreas, and then ovary. Other prevalent types of cancer includeleukemia, central nervous system cancers, including brain cancer,melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neckcancer. Examples 1 through 8 are provided to illustrate contemplatedtherapeutic combinations, and are not intended to limit the scope of theinvention.

Illustrations

The following non-limiting illustrative examples (1 through 9) describevarious cancer diseases and therapeutic approaches that may be used inthe present invention, and are for illustrative purposes only. PreferredMMP inhibitors of the below non-limiting illustrations include but arenot limited to Compound M1, Compound M2, Compound M3, Compound M4,Compound M5, Compound M6, Compound M7, Compound M8, Marimastat,Bay-12-9566, AG-3340, Metastat, and D-2163 (BMS-275291).

Example 1

Lung Cancer

In many countries including Japan, Europe and America, the number ofpatients with lung cancer is fairly large and continues to increase yearafter year and is the most frequent cause of cancer death in both menand women. Although there are many potential causes for lung cancer,tobacco use, and particularly cigarette smoking, is the most important.Additionally, etiologic factors such as exposure to asbestos, especiallyin smokers, or radon are contributory factors. Also occupational hazardssuch as exposure to uranium have been identified as an important factor.Finally, genetic factors have also been identified as another factorthat increase the risk of cancer.

Lung cancers can be histologically classified into non-small cell lungcancers (e.g. squamous cell carcinoma (epidermoid), adenocarcinoma,large cell carcinoma (large cell anaplastic), etc.) and small cell lungcancer (oat cell). Non-small cell lung cancer (NSCLC) has differentbiological properties and responses to chemotherapeutics from those ofsmall cell lung cancer (SCLC). Thus, chemotherapeutic formulas andradiation therapy are different between these two types of lung cancer.

Non-Small Cell Lung Cancer

Where the location of the non-small cell lung cancer tumor can be easilyexcised (stage I and II disease) surgery is the first line of therapyand offers a relatively good chance for a cure. However, in moreadvanced disease (stage IIIa and greater), where the tumor has extendedto tissue beyond the bronchopulmonary lymph nodes, surgery may not leadto complete excision of the tumor. In such cases, the patient's chancefor a cure by surgery alone is greatly diminished. Where surgery willnot provide complete removal of the NSCLC tumor, other types oftherapies must be utilized.

Today radiation therapy is the standard treatment to controlunresectable or inoperable NSCLC. Improved results have been seen whenradiation therapy has been combined with chemotherapy, but gains havebeen modest and the search continues for improved methods of combiningmodalities.

Radiation therapy is based on the principle that high-dose radiationdelivered to a target area will result in the death of reproductivecells in both tumor and normal tissues. The radiation dosage regimen isgenerally defined in terms of radiation absorbed dose (rad), time andfractionation, and must be carefully defined by the oncologist. Theamount of radiation a patient receives will depend on variousconsideration but the two most important considerations are the locationof the tumor in relation to other critical structures or organs of thebody, and the extent to which the tumor has spread. A preferred courseof treatment for a patient undergoing radiation therapy for NSCLC willbe a treatment schedule over a 5 to 6 week period, with a total dose of50 to 60 Gy administered to the patient in a single daily fraction of1.8 to 2.0 Gy, 5 days a week. A Gy is an abbreviation for Gray andrefers to 100 rad of dose.

However, as NSCLC is a systemic disease, and radiation therapy is alocal modality, radiation therapy as a single line of therapy isunlikely to provide a cure for NSCLC, at least for those tumors thathave metastasized distantly outside the zone of treatment. Thus, the useof radiation therapy with other modality regimens have importantbeneficial effects for the treatment of NSCLC.

Generally, radiation therapy has been combined temporally withchemotherapy to improve the outcome of treatment. There are variousterms to describe the temporal relationship of administering radiationtherapy in combination with MMP inhibitors and chemotherapy, and thefollowing examples are the preferred treatment regimens and are providedfor illustration only and are not intended to limit the use of othercombinations. “Sequential” therapy refers to the administration ofchemotherapy and/or MMP therapy and/or radiation therapy separately intime in order to allow the separate administration of eitherchemotherapy and/or MMP inhibitors, and/or radiation therapy.“Concomitants therapy refers to the administration of chemotherap”and/or a MMP inhibitor, and/or radiation therapy on the same day.Finally, “alternating therapy refers to the administration of radiationtherapy on the days in which chemotherapy and/or MMP inhibitor would nothave been administered if it was given alone.

It is reported that advanced non-small cell lung cancers do not respondfavorably to single-agent chemotherapy and useful therapies for advancedinoperable cancers have been limited. (Journal of Clinical oncology,vol. 10, pp. 829-838 (1992)).

Japanese Patent Kokai 5-163293 refers to some specified antibiotics of16-membered-ring macrolides as a drug delivery carrier capable oftransporting anthoracycline-type anticancer drugs into the lungs for thetreatment of lung cancers. However, the macrolide antibiotics specifiedherein are disclosed to be only a drug carrier, and there is noreference to the therapeutic use of macrolides against non-small celllung cancers.

WO 93/18,652 refers to the effectiveness of the specified16-membered-ring macrolides such as bafilomycin, etc. in treatingnon-small cell lung cancers, but they have not yet been clinicallypracticable.

Pharmacology, vol. 41, pp. 177-183 (1990) describes that a long-term useof erythromycin increases productions of interleukins 1, 2 and 4, all ofwhich contribute to host immune responses, but there is no reference tothe effect of this drug on non-small cell lung cancers.

Teratogenesis, Carcinogenesis, and Mutagenesis, vol. 10, pp. 477-501(1990) describes that some of antimicrobial drugs can be used as ananticancer agent, but does not refer to their application to non-smallcell lung cancers.

In addition, interleukins are known to have an antitumor effect, buthave not been reported to be effective against non-small cell lungcancers.

Any 14- or 15-membered-ring macrolides have not been reported to beeffective against non-small cell lung cancers.

However, several chemotherapeutic agents have been shown to beefficacious against NSCLC. Preferred chemotherapeutic agents that can beused in the present invention against NSCLC include etoposide,carboplatin, methotrexate, 5-Fluorouracil, epirubicin, doxorubicin,taxol, inhibitor of normal mitotic activity; and cyclophosphamide. Evenmore preferred chemotherapeutic agents active against NSCLC includecisplatin, ifosfamide, mitomycin C, epirubicin, vinblastine, andvindesine.

Other agents that are under investigation for use against NSCLC include:camptothecins, a topoisomerase 1 inhibitor; navelbine (vinorelbine), amicrotubule assebly inhibitor; gemcitabine, a deoxycytidine analogue;fotemustine, a nitrosourea compound; and edatrexate, a antifol.

The overall and complete response rates for NSCLC has been shown toincrease with use of combination chemotherapy as compared tosingle-agent treatment. Haskel C M: Chest. 99: 1325, 1991; Bakowski M T:Cancer Treat Rev 10:159, 1983; Joss R A: Cancer Treat Rev 11:205, 1984.

A preferred therapy for the treatment of NSCLC is a combination oftherapeutically effective amounts of one or more MMP inhibitors incombination with the following combinations of antineoplastic agents: 1)itosfamide, cisplatin, etoposide; 2) cyclophoshamide, doxorubicin,cisplatin; 3) isofamide, carboplatin, etoposide; 4) bleomycin,etoposide, cisplatin; 5) isofamide, mitomycin, cisplatin; 6) cisplatin,vinblastine; 7) cisplatin, vindesine; 8) mitomycin C, vinblastine,cisplatin; 9) mitomycin C, vindesine, cisplatin; 10) isofamide,etoposide; 11) etoposide, cisplatin; 12) isofamide, mitomycin C; 13)flurouracil, cisplatin, vinblastine; 14) carboplatin, etoposide; orradiation therapy.

Accordingly, apart from the conventional concept of anticancer therapy,there is a strong need for the development of therapies practicablyeffective for the treatment of non-small cell lung cancers.

Small Cell Lung Cancer

Approximately 15 to 20 percent of all cases of lung cancer reportedworldwide is small cell lung cancer (SCLC). Ihde DC: Cancer 54:2722,1984. Currently, treatment of SCLC incorporates multi-modal therapy,including chemotherapy, radiation therapy and surgery. Response rates oflocalized or disseminated SCLC remain high to systemic chemotherapy,however, persistence of the primary tumor and persistence of the tumorin the associated lymph nodes has led to the integration of severaltherapeutic modalities in the treatment of SCLC.

A preferred therapy for the treatment of lung cancer is a combination oftherapeutically effective amounts of one or more MMP inhibitors incombination with the following antineoplastic agents: vincristine,cisplatin, carboplatin, cyclophosphamide, epirubicin (high dose),etoposide (VP-16) I.V., etoposide (VP-16) oral, isofamide, teniposide(VM-26), and doxorubicin. Other preferred single-agents chemotherapeuticagents that may be used in the present invention include BCNU(carmustine), vindesine, hexamethylmelamine (altretamine), methotrexate,nitrogen mustard, and CCNU (lomustine). Other chemotherapeutic agentsunder investigation that have shown activity againe SCLC includeiroplatin, gemcitabine, lonidamine, and taxol. Single-agentchemotherapeutic agents that have not shown activity against SCLCinclude mitoguazone, mitomycin C, aclarubicin, diaziquone, bisantrene,cytarabine, idarubicin, mitomxantrone, vinblastine, PCNU and esorubicin.

The poor results reported from single-agent chemotherapy has led to useof combination chemotherapy.

A preferred therapy for the treatment of NSCLC is a combination oftherapeutically effective amounts of one or more MMP inhibitors incombination with the following combinations of antineoplastic agents: 1)etoposide (VP-16), cisplatin; 2) cyclophosphamide, adrianmycin[(doxorubicin), vincristine, etoposide (VP-16)]; 3) Cyclophosphamide,adrianmycin(doxorubicin), vincristine; 4) Etoposide (VP-16), ifosfamide,cisplatin; 5) etoposide (VP-16), carboplatin; 6) cisplatin, vincristine(Oncovin), doxorubicin, etoposide.

Additionally, radiation therapy in conjunction with the preferredcombinations of MMP inhibitors and/or systemic chemotherapy iscontemplated to be effective at increasing the response rate for SCLCpatients. The typical dosage regimen for radiation therapy ranges from40 to 55 Gy, in 15 to 30 fractions, 3 to 7 times week. The tissue volumeto be irradiated is determined by several factors and generally thehilum and subcarnial nodes, and bilateral mdiastinal nodes up to thethoracic inlet are treated, as well as the primary tumor up to 1.5 to2.0 cm of the margins.

Example 2

Colorectal Cancer

Survival from colorectal cancer depends on the stage and grade of thetumor, for example precursor adenomas to metastatic adenocarcinoma.Generally, colorectal cancer can be treated by surgically removing thetumor, but overall survival rates remain between 45 and 60 percent.Colonic excision morbidity rates are fairly low and is generallyassociated with the anastomosis and not the extent of the removal of thetumor and local tissue. In patients with a high risk of reoccurrence,however, chemotherapy has been incorporated into the treatment regimenin order to improve survival rates.

Tumor metastasis prior to surgery is generally believed to be the causeof surgical intervention failure and up to one year of chemotherapy isrequired to kill the non-excised tumor cells. As severe toxicity isassociated with the chemotherapeutic agents, only patients at high riskof recurrence are placed on chemotherapy following surgery. Thus, theincorporation of an antiangiogenesis inhibitor into the management ofcolorectal cancer will play an important role in the treatment ofcolorectal cancer and lead to overall improved survival rates forpatients diagnosed with colorectal cancer.

A preferred combination therapy for the treatment of colorectal canceris surgery, followed by a regimen of one or more chemotherapeutic agentsand an MMP inhibitor cycled over a one year time period. A morepreferred combination therapy for the treatment of colorectal cancer isa regimen of one or more MMP inhibitors, followed by surgical removal ofthe tumor from the colon or rectum and then followed be a regimen of oneor more chemotherapeutic agents and one or more MMP inhibitors, cycledover a one year time period. An even more preferred therapy for thetreatment of colon cancer is a combination of therapeutically effectiveamounts of one or more MMP inhibitors.

A more preferred therapy for the treatment of colon cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors in combination with the following antineoplastic agents:fluorouracil, and Levamisole. Preferably, fluorouracil and Levamisoleare used in combination.

Example 3

Breast Cancer

Today, among women in the United States, breast cancer remains the mostfrequent diagnosed cancer. One in 8 women in the United States are atrisk of developing breast cancer in their lifetime. Age, family history,diet, and genetic factors have been identified as risk factors forbreast cancer. Breast cancer is the second leading cause of death amongwomen.

Different chemotherapeutic agents are known in art for treating breastcancer. Cytotoxic agents used for treating breast cancer includedoxorubicin, cyclophosphamide, methotrexate, 5-fluorouracil, mitomycinC, mitoxantrone, taxol, and epirubicin. CANCER SURVEYS, Breast Cancervolume 18, Cold Spring Harbor Laboratory Press, 1993.

In the treatment of locally advanced noninflammatory breast cancer, MMPinhibitors can be used to treat the disease in combination with otherMMP inhibitors, or in combination with surgery, radiation therapy,chemotherapeutic agents, or with other antiangiogenic agents. Preferredcombinations of chemotherapeutic agents, radiation therapy and surgerythat can be used in combination with the present invention include, butare not limited to the following combinations: 1) doxorubicin,vincristine, radical mastectomy; 2) doxorubicin, vincristine, radiationtherapy; 3) cyclophosphamide, doxorubicin, 5-flourouracil, vincristine,prednisone, mastecomy; 4) cyclophosphamide, doxorubicin, 5-flourouracil,vincristine, prednisone, radiation therapy; 5) cyclophosphamide,doxorubicin, 5-flourouracil, premarin, tamoxifen, radiation therapy forpathologic complete response; 6) cyclophosphamide, doxorubicin,5-flourouracil, prematin, tamoxifen, mastectomy, radiation therapy forpathologic partial response; 7) mastectomy, radiation therapy,levamisole; 8) mastectomy, radiation therapy; 9) mastectomy,vincristine, doxorubicin, cyclophosphamide, levamisole; 10) mastectomy,vincristine, doxorubicin, cyclophosphamide; 11) mastecomy,cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin,radiation therapy; 12) mastecomy, cyclophosphamide, doxorubicin,5-fluorouracil, tamoxifen, halotestin.

In the treatment of locally advanced inflammatory breast cancer, MMPinhibitors can be used to treat the disease in combination with otherantiangiogenic agents, or in combination with surgery, radiation therapyor with chemotherapeutic agents. Preferred combinations ofchemotherapeutic agents, radiation therapy and surgery that can be usedin combination with the present invention include, but or not limited tothe following combinations: 1) cyclophosphamide, doxorubicin,5-fluorouracil, radiation therapy; 2) cyclophosphamide, doxorubicin,5-fluorouracil, mastectomy, radiation therapy; 3) 5-flurouracil,doxorubicin, clyclophosphamide, vincristine, prednisone, mastectomy,radiation therapy; 4) 5-flurouracil, doxorubicin, clyclophosphamide,vincristine, mastectomy, radiation therapy; 5) cyclophosphamide,doxorubicin, 5-fluorouracil, vincristine, radiation therapy; 6)cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, mastectomy,radiation therapy; 7) doxorubicin, vincristine, methotrexate, radiationtherapy, followed by vincristine, cyclophosphamide, 5-florouracil; 8)doxorubicin, vincristine, cyclophosphamide, methotrexate, 5-florouracil,radiation therapy, followed by vincristine, cyclophosphamide,5-florouracil; 9) surgery, followed by cyclophosphamide, methotrexate,5-fluorouracil, predinsone, tamoxifen, followed by radiation therapy,followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,tamoxifen, doxorubicin, vincristine, tarnoxifen; 10) surgery, followedby cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiationtherapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil,predinsone, tamoxifen, doxorubicin, vincristine, tamoxifen; 11) surgery,followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,tamoxifen, followed by radiation therapy, followed by cyclophosphamide,methotrexate, 5-fluorouracil, doxorubicin, vincristine, tamoxifen; 12)surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil,followed by radiation therapy, followed by cyclophosphamide,methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin,vincristine; 13) surgery, followed by cyclophosphamide, methotrexate,5-fluorouracil, predinsone, tamoxifen, followed by radiation therapy,followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery, followed bycyclophosphamide, methotrexate, 5-fluorouracil, followed by radiationtherapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil,predinsone, tamoxifen, doxorubicin, vincristine; 15) surgery, followedby cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,tamoxifen, followed by radiation therapy, followed by cyclophosphamide,methotrexate, 5-fluorouracil, doxorubicin, vincristine; 16)5-florouracil, doxorubicin, cyclophosphamide followed by mastectomy,followed by 5-florouracil, doxorubicin, cyclophosphamide, followed byradiation therapy.

In the treatment of metastatic breast cancer, MMP inhibitors can be usedto treat the disease in combination with other MMP inhibitors, or incombination with surgery, radiation therapy or with chemotherapeuticagents. Preferred combinations of chemotherapeutic agents that can beused in combination with the angiogenesis inhibitors of the presentinvention include, but are not limited to the following combinations: 1)cyclosphosphamide, methotrexate, 5-fluorouracil; 2) cyclophosphamide,adriamycin, 5-fluorouracil; 3) cyclosphosphamide, methotrexate,5-flurouracil, vincristine, prednisone; 4) adriamycin, vincristine; 5)thiotepa, adriamycin, vinblastine; 6) mitomycin, vinblastine; 7)cisplatin, etoposide.

Example 4

Prostate Cancer

Prostate cancer is now the leading form of cancer among men and thesecond most frequent cause of death from cancer in men. It is estimatedthat more than 165,000 new cases of prostate cancer were diagnosed in1993, and more than 35,000 men died from prostate cancer in that year.Additionally, the incidence of prostate cancer has increased by 50%since 1981, and mortality from this disease has continued to increase.Previously, most men died of other illnesses or diseases before dyingfrom their prostate cancer. We now face increasing morbidity fromprostate cancer as men live longer and the disease has the opportunityto progress.

Current therapies for prostate cancer focus exclusively upon reducinglevels of dihydrotestosterone to decrease or prevent growth of prostatecancer. In addition to the use of digital rectal examination andtransrectal ultrasonography, prostate-specific antigen (PSA)concentration is frequently used in the diagnosis of prostate cancer.

A preferred therapy for the treatment of prostate cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors.

U.S. Pat. No. 4,472,382 discloses treatment of benign prostatichyperplasia (BPH) with an antiandrogen and certain peptides which act asLH-RH agonists.

U.S. Pat. No. 4,596,797 discloses aromatase inhibitors as a method ofprophylaxis and/or treatment of prostatic hyperplasia.

U.S. Pat. No. 4,760,053 describes a treatment of certain cancers whichcombines an LHRH agonist with an antiandrogen and/or an antiestrogenand/or at least one inhibitor of sex steroid biosynthesis.

U.S. Pat. No. 4,775,660 discloses a method of treating breast cancerwith a combination therapy which may include surgical or chemicalprevention of ovarian secretions and administering an antiandrogen andan antiestrogen.

U.S. Pat. No. 4,659,695 discloses a method of treatment of prostatecancer in susceptible male animals including humans whose testicularhormonal secretions are blocked by surgical or chemical means, e.g. byuse of an LHRH agonist, which comprises administering an antiandrogen,e.g. flutamide, in association with at least one inhibitor of sexsteroid biosynthesis, e.g. aminoglutethimide and/or ketoconazole.

Prostate Specific Antigen

One well known prostate cancer marker is Prostate Specific Antigen(PSA). PSA is a protein produced by prostate cells and is frequentlypresent at elevated levels in the blood of men who have prostate cancer.PSA has been shown to correlate with tumor burden, serve as an indicatorof metastatic involvement, and provide a parameter for following theresponse to surgery, irradiation, and androgen replacement therapy inprostate cancer patients. It should be noted that Prostate SpecificAntigen (PSA) is a completely different protein from Prostate SpecificMembrane Antigen (PSMA). The two proteins have different structures andfunctions and should not be confused because of their similarnomenclature.

Prostate Specific Membrane Antigen (PSMA)

In 1993, the molecular cloning of a prostate-specific membrane antigen(PSMA) was reported as a potential prostate carcinoma marker andhypothesized to serve as a target for imaging and cytotoxic treatmentmodalities for prostate cancer. Antibodies against PSMA have beendescribed and examined clinically for diagnosis and treatment ofprostate cancer. In particular, Indium-111 labeled PSMA antibodies havebeen described and examined for diagnosis of prostate cancer anditrium-labelled PSMA antibodies have been described and examined for thetreatment of prostate cancer.

Example 5

Bladder Cancer

The classification of bladder cancer is divided into three mainclasses: 1) superficial disease, 2) muscle-invasive disease, and 3)metastatic disease.

Currently, transurethral resection (TUR), or segmental resection,account for first line therapy of superficial bladder cancer, i.e.,disease confined to the mucosa or the lamina propria. However,intravesical therapies are necessary, for example, for the treatment ofhigh-grade tumors, carcinoma in situ, incomplete resections,recurrences, and multifocal papillary. Recurrence rates range from up to30 to 80 percent, depending on stage of cancer.

Therapies that are currently used as intravesical therapies includechemotherapy, immuontherapy, bacille Calmette-Guerin (BCG) andphotodynamic therapy. The main objective of intravesical therapy istwofold: to prevent recurrence in high-risk patients and to treatdisease that cannot by resected. The use of intravesical therapies mustbe balanced with its potentially toxic side effects. Additionally, BCGrequires an unimpaired-immune system to induce an antitumor effect.Chemotherapeutic agents that are known to be inactive againstsuperficial bladder cancer include Cisplatin, actinomycin D,5-fluorouracil, bleomycin, and cyclophosphamide methotrxate.

In the treatment of superficial bladder cancer, MMP inhibitors can beused to treat the disease in combination with other MMP inhibitors, orin combination with surgery (TUR), chemotherapy and intravesicaltherapies.

A preferred therapy for the treatment of superficial bladder cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors in combination with: thiotepa (30 to 60 mg/day), mitomycin C(20 to 60 mg/day), and doxorubicin (20 to 80 mg/day).

A preferred intravesicle immunotherapeutic agent that may be used in thepresent invention is BCG. A preferred daily dose ranges from 60 to 120mg, depending on the strain of the live attenuated tuberculosis organismused.

A preferred photodynamic therapeutic agent that may be used with thepresent invention is Photofrin I, a photosensitizing agent, administeredintravenously. It is taken up by the low-density lipoprotein receptorsof the tumor cells and is activated by exposure to visible light.Additionally, neomydium YAG laser activation generates large amounts ofcytotoxic free radicals and singlet oxygen.

In the treatment of muscle-invasive bladder cancer, MMP inhibitors canbe used to treat the disease in combination with other MMP inhibitors,or in combination with surgery (TUR), intravesical chemotherapy,radiation therapy, and radical cystectomy with pelvic lymph nodedissection.

A preferred radiation dose for the treatment of bladder cancer isbetween 5,000 to 7,000 cGY in fractions of 180 to 200 cGY to the tumor.Additionally, 3,500 to 4,700 cGY total dose is administered to thenormal bladder and pelvic contents in a four-field technique. Radiationtherapy should be considered only if the patient is not a surgicalcandidate, but may be considered as preoperative therapy.

A preferred combination of surgery and chemotherapeutic agents that canbe used in combination with the MMP inhibitors of the present inventionis cystectomy in conjunction with five cycles of cisplatin (70 to 100mg/m(square)); doxorubicin (50 to 60 mg/m(square); and cyclophosphamide(500 to 600 mg/m(square).

A more preferred therapy for the treatment of superficial bladder canceris a combination of therapeutically effective amounts of one or more MMPinhibitors.

An even more preferred combination for the treatment of superficialbladder cancer is a combination of therapeutically effective amounts ofone or more MMP inhibitors in combination with the followingcombinations of antineoplastic agents: 1) cisplatin, doxorubicin,cyclophosphamide; and 2) cisplatin, 5-fluorouracil. An even morepreferred combination of chemotherapeutic agents that can be used incombination with radiation therapy and MMP inhibitors is a combinationof cisplatin, methotrexate, vinblastine.

Currently no curative therapy exists for metastatic bladder cancer. Thepresent invention contemplates an effective treatment of bladder cancerleading to improved tumor inhibition or regression, as compared tocurrent therapies.

In the treatment of metastatic bladder cancer, MMP inhibitors can beused to treat the disease in combination with other MMP inhibitors, orin combination with surgery, radiation therapy or with chemotherapeuticagents.

A preferred therapy for the treatment of metastatic bladder cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors.

A more preferred combination for the treatment of metastatic bladdercancer is a combination of therapeutically effective amounts of one ormore MMP inhibitors in combination with the following antineoplasitcagents: 1) cisplatin and methotrexate; 2) doxorubicin, vinblastine,cyclophoshamide, and 5-fluorouracil; 3) vinblastine, doxorubicin,cisplatin, methotrexate; 4) vinblastine, cisplatin, methotrexate; 5)cyclophosphamide, doxorubicin, cisplatin; 6) 5-fluorouracil, cisplatin.

Example 6

Pancreas Cancer

Approximately 2% of new cancer cases diagnoses in the United States ispancreatic cancer. Pancreatic cancer is generally classified into twoclinical types: 1) adenocarcinoma (metastatic and non-metastatic), and2) cystic neoplasms (serous cystadenomas, mucinous cystic neoplasms,papilary cystic neoplasms, acinar cell systadenocarcinoma, cysticchoriocarcinoma, cystic teratomas, angiomatous neoplasms).

Preferred combinations of therapy for the treatment of non-metastaticadenocarcinoma that may be used in the present invention include the useof an MMP inhibitor along with preoperative bilary tract decompression(patients presenting with obstructive jaundice); surgical resection,including standard resection, extended or radial resection and distalpancreatectomy (tumors of body and tail); adjuvant radiation;antiangiogenic therapy; and chemotherapy.

For the treatment of metastatic adenocarcinoma, a preferred combinationtherapy consists of an MMP inhibitor of the present invention incombination with continuous treatment of 5-fluorouracil, followed byweekly cisplatin therapy.

A more preferred combination therapy for the treatment of cysticneoplasms is the use of an MMP inhibitor along with resection.

Example 7

Ovary Cancer

Celomic epithelial carcinoma accounts for approximately 90% of ovariancancer cases. A preferred therapy for the treatment of ovary cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors.

Preferred single agents that can be used in combination with an MMPinhibitor include, but are not limited to: alkylating agents,ifosfamide, cisplatin, carboplatin, taxol, doxorubicin, 5-fluorouracil,methotrexate, mitomycin, hexamethylmelamine, progestins, antiestrogens,prednimustine, dihydroxybusulfan, galactitol, interferon alpha, andinterferon gama.

Preferred combinations for the treatment of celomic epithelial carcinomais a combination of therapeutically effective amounts of one or more MMPinhibitors in combination with the following combinations ofantineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2)hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3)cyclophosphamide, hexamehtylmelamine, 5-flurouracil, cisplatin; 4)melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan,doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin,carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine,cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine,carboplatin; 9) cyclophosphamide, cisplatin; 10) hexamethylmelamine,doxorubicin, carboplatin; 11) cyclophosphamide, hexamethlmelamine,doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13)cisplatin, cyclophosphamide.

Germ cell ovarian cancer accounts for approximately 5% of ovarian cancercases. Germ cell ovarian carcinomas are classified-into two maingroups: 1) dysgerminoma, and nondysgerminoma. Nondysgerminoma is furtherclassified into teratoma, endodermal sinus tumor, embryonal carcinoma,chloricarcinoma, polyembryoma, and mixed cell tumors.

A preferred therapy for the treatment of germ cell carcinoma is acombination of therapeutically effective amounts of one or more MMPinhibitors.

A more preferred therapy for the treatment of germ cell carcinoma is acombination of therapeutically effective amounts of one or more MMPinhibitors in combination with one or more of the following combinationsof antineoplastic agents: 1) vincristine, actinomycin D,cyclophosphamide; 2) bleomycin, etoposide, cisplatin; 3) vinblastine,bleomycin, cisplatin.

Cancer of the fallopian tube is the least common type of ovarian cancer,accounting for approximately 400 new cancer cases per year in the UnitedStates. Papillary serous adenocarcinoma accounts for approximately 90%of all malignancies of the ovarian tube.

A preferred therapy for the treatment of fallopian tube cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors.

A more preferred therapy for the treatment of fallopian tube cancer is acombination of therapeutically effective amounts of one or more MMPinhibitors in combination with the following of antineoplastic agents:alkylating agents, ifosfamide, cisplatin, carboplatin, taxol,doxorubicin, 5-fluorouracil, methotrexate, mitomycin,hexamethylmelamine, progestins, antiestrogens, prednimustine,dihydroxybusulfan, galactitol, interferon alpha, and interferon gama.

An even more preferred therapy for the treatment of fallopian tubecancer is a combination of therapeutically effective amounts of one ormore MMP inhibitors in combination with the following combinations ofantineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2)hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3)cyclophosphamide, hexamehtylmelamine, 5-flurouracil, cisplatin; 4)melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan,doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin,carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine,cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine,carboplatin; 9) cyclophQsphamide, cisplatin; 10) hexamethylmelamine,doxorubicin, carboplatin; 11) cyclophosphamide, hexamethlmelamine,doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13)cisplatin, cyclophosphamide.

Example 8

Central Nervous System Cancers

Central nervous system cancer accounts for approximately 2% of newcancer cases in the United States. Common intracranial neoplasms includeglioma, meninginoma, neurinoma, and adenoma.

A preferred therapy for the treatment of central nervous system cancersis a combination of therapeutically effective amounts of one or more MMPinhibitors.

A preferred therapy for the treatment of malignant glioma is acombination of therapeutically effective amounts of one or more MMPinhibitors in combination with the following combinations of therapiesand antineoplastic agents: 1) radiation therapy, BCNU (carmustine); 2)radiation therapy, methyl CCNU (lomustine); 3) radiation therapy, medol;4) radiation therapy, procarbazine; 5) radiation therapy, BCNU, medrol;6) hyperfraction radiation therapy, BCNU; 7) radiation therapy,misonidazole, BCNU; 8) radiation therapy, streptozotocin; 9) radiationtherapy, BCNU, procarbazine; 10) radiation therapy, BCNU, hydroxyurea,procarbazine, VM-26; 11) radiation therapy, BNCU, 5-flourouacil; 12)radiation therapy, Methyl CCNU, dacarbazine; 13) radiation therapy,misonidazole, BCNU; 14) diaziquone; 15) radiation therapy, PCNU; 16)procarbazine (matulane), CCNU, vincristine. A preferred dose ofradiation therapy is about 5,500 to about 6,000 cGY. Preferredradiosensitizers include misonidazole, intra-arterial Budr andintravenous iododeoxyuridine (IUdR). It is also contemplated thatradiosurgery may be used in combinations with antiangiogenesis agents.

Example 9

Additional examples of combinations are listed in Table No 17, below.

TABLE 17 Combination therapies MMP Antineoplastic Inhibitor AgentIndication Compound M1 Anastrozole Breast Compound M1 CapecitabineBreast Compound M1 Docetaxel Breast Compound M1 Gemcitabine Breast,Pancreas Compound M1 Letrozole Breast Compound M1 Megestrol BreastCompound M1 Paclitaxel Breast Compound M1 Tamoxifen Breast Compound M1Toremifene Breast Compound M1 Vinorelbine Breast, Lung Compound M1Topotecan Lung Compound M1 Etoposide Lung Compound M1 Fluorouracil ColonCompound M1 Irinotecan (CPT- Colon, Bladder 11) Compound M1 RetinoidsColon Compound M1 DFMO Colon Compound M1 Ursodeoxycholic Colon acidCompound M1 calcium Colon carbonate Compound M1 selenium Colon CompoundM1 sulindac sulfone Colon Compound M1 Carboplatin Brain Compound M1Goserelin Prostate Acetate Compound M1 Cisplatin Compound M1Ketoconazole Prostate Compound M2 Anastrozole Breast Compound M2Capecitabine Breast Compound M2 Docetaxel Breast Compound M2 GemcitabineBreast, Pancreas Compound M2 Letrozole Breast Compound M2 MegestrolBreast Compound M2 Paclitaxel Breast Compound M2 Tamoxifen BreastCompound M2 Toremifene Breast Compound M2 Vinorelbine Breast, LungCompound M2 Topotecan Lung Compound M2 Etoposide Lung Compound M2Fluorouracil Colon Compound M2 Irinotecan (CPT- Colon, Bladder 11)Compound M2 Retinoids Colon Compound M2 DFMO Colon Compound M2Ursodeoxycholic Colon acid Compound M2 calcium Colon carbonate CompoundM2 selenium Colon Compound M2 sulindac sulfone Colon Compound M2Carboplatin Brain Compound M2 Goserelin Prostate Acetate Compound M2Cisplatin Compound M2 Ketoconazole Prostate Compound M3 AnastrozoleBreast Compound M3 Capecitabine Breast Compound M3 Docetaxel BreastCompound M3 Gemcitabine Breast, Pancreas Compound M3 Letrozole BreastCompound M3 Megestrol Breast Compound M3 Paclitaxel Breast Compound M3Tamoxifen Breast Compound M3 Toremifene Breast Compound M3 VinorelbineBreast, Lung Compound M3 Topotecan Lung Compound M3 Etoposide LungCompound M3 Fluorouracil Colon Compound M3 Irinotecan (CPT- Colon,Bladder 11) Compound M3 Retinoids Colon Compound M3 DFMO Colon CompoundM3 Ursodeoxycholic Colon acid Compound M3 calcium Colon carbonateCompound M3 selenium Colon Compound M3 sulindac sulfone Colon CompoundM3 Carboplatin Brain Compound M3 Goserelin Prostate Acetate Compound M3Cisplatin Compound M3 Ketoconazole Prostate Compound M4 AnastrozoleBreast Compound M4 Capecitabine Breast Compound M4 Docetaxel BreastCompound M4 Gemcitabine Breast, Pancreas Compound M4 Letrozole BreastCompound M4 Megestrol Breast Compound M4 Paclitaxel Breast Compound M4Tamoxifen Breast Compound M4 Toremifene Breast Compound M4 VinorelbineBreast, Lung Compound M4 Topotecan Lung Compound M4 Etoposide LungCompound M4 Fluorouracil Colon Compound M4 Irinotecan (CPT- Colon,Bladder 11) Compound M4 Retinoids Colon Compound M4 DFMO Colon CompoundM4 Ursodeoxycholic Colon acid Compound M4 calcium Colon carbonateCompound M4 selenium Colon Compound M4 sulindac sulfone Colon CompoundM4 Carboplatin Brain Compound M4 Goserelin Prostate Acetate Compound M4Cisplatin Compound M4 Ketoconazole Prostate Compound M5 AnastrozoleBreast Compound M5 Capecitabine Breast Compound M5 Docetaxel BreastCompound M5 Gemcitabine Breast, Pancreas Compound M5 Letrozole BreastCompound M5 Megestrol Breast Compound M5 Paclitaxel Breast Compound M5Tamoxifen Breast Compound M5 Toremifene Breast Compound M5 VinorelbineBreast, Lung Compound M5 Topotecan Lung Compound M5 Etoposide LungCompound M5 Fluorouracil Colon Compound M5 Irinotecan (CPT- Colon,Bladder 11) Compound M5 Retinoids Colon Compound M5 DFMO Colon CompoundM5 Ursodeoxycholic Colon acid Compound M5 calcium Colon carbonateCompound M5 selenium Colon Compound M5 sulindac sulfone Colon CompoundM5 Carboplatin Brain Compound M5 Goserelin Prostate Acetate Compound M5Cisplatin Compound M5 Ketoconazole Prostate Compound M7 AnastrozoleBreast Compound M7 Capecitabine Breast Compound M7 Docetaxel BreastCompound M7 Gemcitabine Breast, Pancreas Compound M7 Letrozole BreastCompound M7 Megestrol Breast Compound M7 Paclitaxel Breast Compound M7Tamoxifen Breast Compound M7 Toremifene Breast Compound M7 VinorelbineBreast, Lung Compound M7 Topotecan Lung Compound M7 Etoposide LungCompound M7 Fluorouracil Colon Compound M7 Irinotecan (CPT- Colon,Bladder 11) Compound M7 Retinoids Colon Compound M7 DFMO Colon CompoundM7 Ursodeoxycholic Colon acid Compound M7 calcium Colon carbonateCompound M7 selenium Colon Compound M7 sulindac sulfone Colon CompoundM7 Carboplatin Brain Compound M7 Goserelin Prostate Acetate Compound M7Cisplatin Compound M7 Ketoconazole Prostate Marimastat AnastrozoleBreast Marimastat Capecitabine Breast Marimastat Docetaxel BreastMarimastat Gemcitabine Breast, Pancreas Marimastat Letrozole BreastMarimastat Megestrol Breast Marimastat Paclitaxel Breast MarimastatTamoxifen Breast Marimastat Toremifene Breast Marimastat VinorelbineBreast, Lung Marimastat Topotecan Lung Marimastat Etoposide LungMarimastat Fluorouracil Colon Marimastat Irinotecan (CPT- Colon, Bladder11) Marimastat Retinoids Colon Marimastat DFMO Colon MarimastatUrsodeoxycholic Colon acid Marimastat calcium Colon carbonate Marimastatselenium Colon Marimastat sulindac sulfone Colon Marimastat CarboplatinBrain Marimastat Goserelin Prostate Acetate Marimastat CisplatinMarimastat Ketoconazole Prostate Bay-12-9566 Anastrozole BreastBay-12-9566 Capecitabine Breast Bay-12-9566 Docetaxel Breast Bay-12-9566Gemcitabine Breast, Pancreas Bay-12-9566 Letrozole Breast Bay-12-9566Megestrol Breast Bay-12-9566 Paclitaxel Breast Bay-12-9566 TamoxifenBreast Bay-12-9566 Toremifene Breast Bay-12-9566 Vinorelbine Breast,Lung Bay-12-9566 Topotecan Lung Bay-12-9566 Etoposide Lung Bay-12-9566Fluorouracil Colon Bay-12-9566 Irinotecan (CPT- Colon, Bladder 11)Bay-12-9566 Retinoids Colon Bay-12-9566 DFMO Colon Bay-12-9566Ursodeoxycholic Colon acid Bay-12-9566 calcium Colon carbonateBay-12-9566 selenium Colon Bay-12-9566 sulindac sulfone ColonBay-12-9566 Carboplatin Brain Bay-12-9566 Goserelin Prostate AcetateBay-12-9566 Cisplatin Bay-12-9566 Ketoconazole Prostate AG-3340Anastrozole Breast AG-3340 Capecitabine Breast AG-3340 Docetaxel BreastAG-3340 Gemcitabine Breast, Pancreas AG-3340 Letrozole Breast AG-3340Megestrol Breast AG-3340 Paclitaxel Breast AG-3340 Tamoxifen BreastAG-3340 Toremifene Breast AG-3340 Vinorelbine Breast, Lung AG-3340Topotecan Lung AG-3340 Etoposide Lung AG-3340 Fluorouracil Colon AG-3340Irinotecan (CPT- Colon, Bladder 11) AG-3340 Retinoids Colon AG-3340 DFMOColon AG-3340 Ursodeoxycholic Colon acid AG-3340 calcium Colon carbonateAG-3340 selenium Colon AG-3340 sulindac sulfone Colon AG-3340Carboplatin Brain AG-3340 Goserelin Prostate Acetate AG-3340 CisplatinAG-3340 Ketoconazole Prostate Metastat Anastrozole Breast MetastatCapecitabine Breast Metastat Docetaxel Breast Metastat GemcitabineBreast, Pancreas Metastat Letrozole Breast Metastat Megestrol BreastMetastat Paclitaxel Breast Metastat Tamoxifen Breast Metastat ToremifeneBreast Metastat Vinorelbine Breast, Lung Metastat Topotecan LungMetastat Etoposide Lung Metastat Fluorouracil Colon Metastat Irinotecan(CPT- Colon, Bladder 11) Metastat Retinoids Colon Metastat DFMO ColonMetastat Ursodeoxycholic Colon acid Metastat calcium Colon carbonateMetastat selenium Colon Metastat sulindac sulfone Colon MetastatCarboplatin Brain Metastat Goserelin Prostate Acetate Metastat CisplatinMetastat Ketoconazole Prostate D-2163 Anastrozole Breast D-2163Capecitabine Breast D-2163 Docetaxel Breast D-2163 Gemcitabine Breast,Pancreas D-2163 Letrozole Breast D-2163 Megestrol Breast D-2163Paclitaxel Breast D-2163 Tamoxifen Breast D-2163 Toremifene BreastD-2163 Vinorelbine Breast, Lung D-2163 Topotecan Lung D-2163 EtoposideLung D-2163 Fluorouracil Colon D-2163 Irinotecan (CPT- Colon, Bladder11) D-2163 Retinoids Colon D-2163 DFMO Colon D-2163 UrsodeoxycholicColon acid D-2163 calcium Colon carbonate D-2163 selenium Colon D-2163sulindac sulfone Colon D-2163 Carboplatin Brain D-2163 GoserelinProstate Acetate D-2163 Cisplatin D-2163 Ketoconazole ProstateAdditional examples of combinations are listed in Table No 18, below.

TABLE 18 Additional combination therapies MMP Inhibitor AntineoplasticAgents Indication Compound M1 Doxorubicin and Breast CyclophosphamideCompound M1 Cyclophosphamide, Breast Doxorubicin, and FluorouracilCompound M1 Cyclophosphamide, Breast Fluorouracil and MitoxantroneCompound M1 Mitoxantrone, Flourouracil Breast and Leucovorin Compound M1Vinblastine, Doxorubicin, Breast Thiotepa, and Fluoxymestrone CompoundM1 Cyclophosphamide, Breast Methotrexate Fluorouracil Compound M1Doxorubicin, Breast Cyclophosphamide, Methotrexate, FluorouracilCompound M1 Vinblastine, Breast Doxorubicin, Thiotepa, FluoxymesteroneCompound M1 Fluorouracil, Levamisole Colon Compound M1 Leucovorin,Fluorouracil Colon Compound M1 Cyclophosphamide, Lung Doxorubicin,Etoposide Compound M1 Cyclophosphamide, Lung Doxorubicin, VincristineCompound M1 Etoposide, Carboplatin Lung Compound M1 Etoposide, CisplatinLung Compound M1 Paclitaxel, Carboplatin Lung Compound M1 Gemcitabine,Cisplatin Lung Compound M1 Paclitaxel, Cisplatin Lung Compound M2Doxorubicin and Breast Cyclophosphamide Compound M2 Cyclophosphamide,Breast Doxorubicin, and Fluorouracil Compound M2 Cyclophosphamide,Breast Fluorouracil and Mitoxantrone Compound M2 Mitoxantrone,Flourouracil Breast and Leucovorin Compound M2 Vinblastine, Doxorubicin,Breast Thiotepa, and Fluoxymestrone Compound M2 Cyclophosphamide, BreastMethotrexate, Fluorouracil Compound M2 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Compound M2 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Compound M2 Fluorouracil,Levamisole Colon Compound M2 Leucovorin, Fluorouracil Colon Compound M2Cyclophosphamide, Lung Doxorubicin, Etoposide Compound M2Cyclophosphamide, Lung Doxorubicin, Vincristine Compound M2 Etoposide,Carboplatin Lung Compound M2 Etoposide, Cisplatin Lung Compound M2Paclitaxel, Carboplatin Lung Compound M2 Gemcitabine, Cisplatin LungCompound M2 Paclitaxel, Cisplatin Lung Compound M3 Doxorubicin andBreast Cyclophosphamide Compound M3 Cyclophosphamide, BreastDoxorubicin, and Fluorouracil Compound M3 Cyclophosphamide, BreastFluorouracil and Mitoxantrone Compound M3 Mitoxantrone, FlourouracilBreast and Leucovorin Compound M3 Vinblastine, Doxorubicin, BreastThiotepa, and Fluoxymestrone Compound M3 Cyclophosphamide, BreastMethotrexate, Fluorouracil Compound M3 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Compound M3 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Compound M3 Fluorouracil,Levamisole Colon Compound M3 Leucovorin, Fluorouracil Colon Compound M3Cyclophosphamide, Lung Doxorubicin, Etoposide Compound M3Cyclophosphamide, Lung Doxorubicin, Vincristine Compound M3 Etoposide,Carboplatin Lung Compound M3 Etoposide, Cisplatin Lung Compound M3Paclitaxel, Carboplatin Lung Compound M3 Gemcitabine, Cisplatin LungCompound M3 Paclitaxel, Cisplatin Lung Compound M4 Doxorubicin andBreast Cyclophosphamide Compound M4 Cyclophosphamide, BreastDoxorubicin, and Fluorouracil Compound M4 Cyclophosphamide, BreastFluorouracil and Mitoxantrone Compound M4 Mitoxantrone, FlourouracilBreast and Leucovorin Compound M4 Vinblastine, Doxorubicin, BreastThiotepa, and Fluoxymestrone Compound M4 Cyclophosphamide, BreastMethotrexate, Fluorouracil Compound M4 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Compound M4 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Compound M4 Fluorouracil,Levamisole Colon Compound M4 Leucovorin, Fluorouracil Colon Compound M4Cyclophosphamide, Lung Doxorubicin, Etoposide Compound M4Cyclophosphamide, Lung Doxorubicin, Vincristine Compound M4 Etoposide,Carboplatin Lung Compound M4 Etoposide, Cisplatin Lung Compound M4Paclitaxel, Carboplatin Lung Compound M4 Gemcitabine, Cisplatin LungCompound M4 Paclitaxel, Cisplatin Lung Compound M5 Doxorubicin andBreast Cyclophosphamide Compound M5 Cyclophosphamide, BreastDoxorubicin, and Fluorouracil Compound M5 Cyclophosphamide, BreastFluorouracil and Mitoxantrone Compound M5 Mitoxantrone, FlourouracilBreast and Leucovorin Compound M5 Vinblastine, Doxorubicin, BreastThiotepa, and Fluoxymestrone Compound M5 Cyclophosphamide, BreastMethotrexate, Fluorouracil Compound M5 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Compound M5 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Compound M5 Fluorouracil,Levamisole Colon Compound M5 Leucovorin, Fluorouracil Colon Compound M5Cyclophosphamide, Lung Doxorubicin, Etoposide Compound M5Cyclophosphamide, Lung Doxorubicin, Vincristine Compound M5 Etoposide,Carboplatin Lung Compound M5 Etoposide, Cisplatin Lung Compound M5Paclitaxel, Carboplatin Lung Compound M5 Gemcitabine, Cisplatin LungCompound M5 Paclitaxel, Cisplatin Lung Compound M7 Doxorubicin andBreast Cyclophosphamide Compound M7 Cyclophosphamide, BreastDoxorubicin, and Fluorouracil Compound M7 Cyclophosphamide, BreastFluorouracil and Mitoxantrone Compound M7 Mitoxantrone, FlourouracilBreast and Leucovorin Compound M7 Vinblastine, Doxorubicin, BreastThiotepa, and Fluoxymestrone Compound M7 Cyclophosphamide, BreastMethotrexate, Fluorouracil Compound M7 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Compound M7 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Compound M7 Fluorouracil,Levamisole Colon Compound M7 Leucovorin, Fluorouracil Colon Compound M7Cyclophosphamide, Lung Doxorubicin, Etoposide Compound M7Cyclophosphamide, Lung Doxorubicin, Vincristine Compound M7 Etoposide,Carboplatin Lung Compound M7 Etoposide, Cisplatin Lung Compound M7Paclitaxel, Carboplatin Lung Compound M7 Gemcitabine, Cisplatin LungCompound M7 Paclitaxel, Cisplatin Lung Bay-12-9566 Doxorubicin andBreast Cyclophosphamide Bay-12-9566 Cyclophosphamide, BreastDoxorubicin, and Fluorouracil Bay-12-9566 Cyclophosphamide, BreastFluorouracil and Mitoxantrone Bay-12-9566 Mitoxantrone, FlourouracilBreast and Leucovorin Bay-12-9566 Vinblastine, Doxorubicin, BreastThiotepa, and Fluoxymestrone Bay-12-9566 Cyclophosphamide, BreastMethotrexate, Fluorouracil Bay-12-9566 Doxorubicin, BreastCyclophosphamide, Methotrexate, Fluorouracil Bay-12-9566 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone Bay-12-9566 Fluorouracil,Levamisole Colon Bay-12-9566 Leucovorin, Fluorouracil Colon Bay-12-9566Cyclophosphamide, Lung Doxorubicin, Etoposide Bay-12-9566Cyclophosphamide, Lung Doxorubicin, Vincristine Bay-12-9566 Etoposide,Carboplatin Lung Bay-12-9566 Etoposide, Cisplatin Lung Bay-12-9566Paclitaxel, Carboplatin Lung Bay-12-9566 Gemcitabine, Cisplatin LungBay-12-9566 Paclitaxel, Cisplatin Lung Metastat Doxorubicin and BreastCyclophosphamide Metastat Cyclophosphamide, Breast Doxorubicin, andFluorouracil Metastat Cyclophosphamide, Breast Fluorouracil andMitoxantrone Metastat Mitoxantrone, Flourouracil Breast and LeucovorinMetastat Vinblastine, Doxorubicin, Breast Thiotepa, and FluoxymestroneMetastat Cyclophosphamide, Breast Methotrexate, Fluorouracil MetastatDoxorubicin, Breast Cyclophosphamide, Methotrexate, FluorouracilMetastat Vinblastine, Breast Doxorubicin, Thiotepa, FluoxymesteroneMetastat Fluorouracil, Levamisole Colon Metastat Leucovorin,Fluorouracil Colon Metastat Cyclophosphamide, Lung Doxorubicin,Etoposide Metastat Cyclophosphamide, Lung Doxorubicin, VincristineMetastat Etoposide, Carboplatin Lung Metastat Etoposide, Cisplatin LungMetastat Paclitaxel, Carboplatin Lung Metastat Gemcitabine, CisplatinLung Metastat Paclitaxel, Cisplatin Lung D-2163 Doxorubicin and BreastCyclophosphamide D-2163 Cyclophosphamide, Breast Doxorubicin, andFluorouracil D-2163 Cyclophosphamide, Breast Fluorouracil andMitoxantrone D-2163 Mitoxantrone, Flourouracil Breast and LeucovorinD-2163 Vinblastine, Doxorubicin, Breast Thiotepa, and FluoxymestroneD-2163 Cyclophosphamide, Breast Methotrexate, Fluorouracil D-2163Doxorubicin, Breast Cyclophosphamide, Methotrexate, Fluorouracil D-2163Vinblastine, Breast Doxorubicin, Thiotepa, Fluoxymesterone D-2163Fluorouracil, Levamisole Colon D-2163 Leucovorin, Fluorouracil ColonD-2163 Cyclophosphamide, Lung Doxorubicin, Etoposide D-2163Cyclophosphamide, Lung Doxorubicin, Vincristine D-2163 Etoposide,Carboplatin Lung D-2163 Etoposide, Cisplatin Lung D-2163 Paclitaxel,Carboplatin Lung D-2163 Gemcitabine, Cisplatin Lung D-2163 Paclitaxel,Cisplatin Lung D-1927 Doxorubicin and Breast Cyclophosphamide D-1927Cyclophosphamide, Breast Doxorubicin, and Fluorouracil D-1927Cyclophosphamide, Breast Fluorouracil and Mitoxantrone D-1927Mitoxantrone, Flourouracil Breast and Leucovorin D-1927 Vinblastine,Doxorubicin, Breast Thiotepa, and Fluoxymestrone D-1927Cyclophosphamide, Breast Methotrexate, Fluorouracil D-1927 Doxorubicin,Breast Cyclophosphamide, Methotrexate, Fluorouracil D-1927 Vinblastine,Breast Doxorubicin, Thiotepa, Fluoxymesterone D-1927 Fluorouracil,Levamisole Colon D-1927 Leucovorin, Fluorouracil Colon D-1927Cyclophosphamide, Lung Doxorubicin, Etoposide D-1927 Cyclophosphamide,Lung Doxorubicin, Vincristine D-1927 Etoposide, Carboplatin Lung D-1927Etoposide, Cisplatin Lung D-1927 Paclitaxel, Carboplatin Lung D-1927Gemcitabine, Cisplatin Lung D-1927 Paclitaxel, Cisplatin Lung

Biological Evaluation

MMP Inhibitors

1. Pancreatic Cell (PC-3) Model:

In this study, the test groups were a vehicle control, Compound M14,Compound M14 with cisplatin and cisplatin alone with n=10 for eachgroup. The tumors were measured with a caliper and the volume calculatedusing the formula for the volume of an elipsoid. The cisplatin dose was10 mpk administered by the intraperitonal route on day 8 post injecionof tumor cells Compound M14, 50 mpk, was first administered about 6:00pm the evening of the same day that the tumor cells were injected in themorning. The same dose of Compound M14 was administered bid for eachfollowing day. Tumor volume (mm³) was measured on day 25. The data belowclearly show an improved response with the combination of the MMPinhibitor and cisplatin.

PC3 Model MMP Inhibitor Combination Study Results Agent AdministeredTumor Volume at Day 25 PC3 Model (mm³) vehicle 860 cisplatin 630Compound M14 480 Compound M14 110 with cisplatin2. Breast Tumor Model:

This study was carried out essentially as PC-3 model. MX-1 breast tumorpieces were implanted (with a trocar) into nude mice with n=10 pergroup. Dosing with Compound M14 (10 mpk or 50 mpk, PO bid) was initiatedwhen the tumors reached a size of 60-120 mg. Dosing was continued for 26days. Taxol was administered at a dose of 9 mpk for the first five daysfollowing the start of dosing by the interperitonal route. The tumorswere measured using a caliper and the volume calculated using theformula for the volume of an elipsoid. The results tabulated belowclearly show an improved response with combination therapy. An improvedresponse is obtained with lower doses Compound M14.

MX-1 Model MMP Inhibitor Combination Study Results Tumor Volume at Day25 Agent Administered (mm³) vehicle 1920 taxol 1280 Compound M14 960 @10 mpk Compound M14 1260 @ 50 mpk Compound M14 @ 50 mpk + 480 taxol @ 9mpk Compound M14 @ 10 mpk + 240 taxol @ 9 mpk3. MX-1 Adjuvant Model:

Mice were implanted with MX-1 tumors and allowed to grow to 50-100 mm3.The animals were dosed with cyclophosphamide (100 or 80 mpk). This wasconsidered Day 1. Two weeks later the animals were pair matched aftertumor regression and dosing BID with the MMPI was begun until the end ofthe experiment. Tumors were measured weekly. The endpoint for the studywas a final tumor size of 1.5 g.

Cyclo- phosphamide MMPI Dose Dose (mpk) MMPI (mpk) MDS sem saline 23.91.3 cyclophosphamide 100 39.5 1.2 cyclophosphamide 80 37.2 1.5cyclophosphamide 100 Compound 200 52.7 2.9 M14 cyclophosphamide 100Compound 50 43.7 1.6 M14 cyclophosphamide 0 Compound 200 53.9 2.9 M14cyclophosphamide 80 Compound 50 44.2 1.8 M14MDS=mean days to tumor weight of 1.5 g4. MX-1 Breast Tumor with Taxol:

Mice were implanted with MX-1 tumors and allowed to grow to 50-100 mg.The animals were pair matched and this was considered Day 1. Treatmentwith MMPI was begun BID on Day 1 until the end of the experiment. Taxolwas injected IP (15 or 9 mpk) QD for 5 days (days 1-5). Tumors weremeasured weekly until an endpoint of 1.5 g was reached.

Taxol MMPI Dose Dose (mpk) MMPI (mpk) MDS sem vehicle 25.3 0.8 mmpiCompound 100 32.2 2.8 M14 mmpi Compound 20 34.7 3 M14 taxol + mmpi 18Compound 56 11 M14 taxol + mmpi 9 Compound 30.1 1.8 M14 taxol + mmpi 18Compound 100 61 M14 taxol + mmpi 9 Compound 100 46.7 3.7 M14 taxol +mmpi 18 Compound 20 59.3 7 M14 taxol + mmpi 9 Compound 20 39.3 1.9 M14MDS = 1.5 g5. SK-mes Tumor with Taxol

Mice were implanted with SK-mes tumors and allowed to grow to 50-100 mg.The animals were pair matched and this was considered Day 1. Treatmentwith MMPI was begun BID on Day 1 until the end of the experiment. Taxolwas injected IP (18 or 9 mpk) QD for 5 days (days 1-5). Tumors weremeasured weekly until an endpoint of 1.0 g was reached.

Taxol MMPI Dose Dose (mpk) MMPI (mpk) MDS sem vehicle 21.2 2.1 mmpiCompound 100 24.7 1.6 M14 mmpi Compound 20 18 1.1 M14 taxol 18 31.5 2.4taxol 9 26.1 2.3 taxol + mmpi 18 Compound 100 43 4 M14 taxol + mmpi 9Compound 100 34.8 1.9 M14 taxol + mmpi 18 Compound 20 39.5 3.6 M14taxol + mmpi 9 Compound 20 34.1 5.7 M14 MDS = 1.0 g6. HT-29 Tumor with Irinotecan

Mice were implanted with HT-29 tumors and allowed to grow to 50-100 mg.The animals were pair matched and this was considered Day 1. Treatmentwith MMPI was begun BID on Day 1 until the end of the experiment.Irinotecan was injected IP (100 or 50 mpk) QD for 5 days (days 1-5).Tumors were measured weekly until an endpoint of 1.0 g was reached.

Irinotecan MMPI Dose Dose (mpk) MMPI (mpk) MDS SEM vehicle 36.4 4.3 mmpiCompound 100 37.9 5.0 M14 mmpi Compound 20 36 4.2 M14 Irinotecan 10036.7 2.6 Irinotecan 50 38.1 3.0 Irinotecan + mmpi 100 Compound 100 51.44.4 M14 Irinotecan + mmpi 50 Compound 100 44.4 4.0 M14 Irinotecan + mmpi100 Compound 20 40.6 4.7 M14 Irinotecan + mmpi 50 Compound 20 36.1 3.0M14 MDS = 1.0 g

1. A combination comprising (a) a matrix metalloproteinase inhibitor and(b) an antineoplastic agent selected from the group consisting ofirinotecan, topotecan and combinations thereof, in amounts effective,when used in a combination therapy, for treatment of a neoplasiadisorder.
 2. The combination of claim 1 wherein the matrixmetalloproteinase inhibitor is an inhibitor of gelatinase.
 3. Thecombination of claim 1 wherein the matrix metalloproteinase inhibitorinhibits at least one of MMP-2 and MMP-9.
 4. The combination of claim 1wherein the matrix metalloproteinase inhibitor is a hydroxamatecompound.
 5. The combination of claim 1 wherein the matrixmetalloproteinase inhibitor is selected from the group consisting ofmarimastat, batimastat, AG-3340, doxycycline and pharmaceuticallyacceptable salts thereof.
 6. A method for treating a neoplasia disorderin a mammal, the method comprising administering to the mammal atherapeutically effective amount of a combination of claim 1 comprising(a) a matrix metalloproteinuse inhibitor and (b) an antineoplastic agentselected from the group consisting of irinotecan, topotecan andcombinations thereof.
 7. The method of claim 6 wherein the matrixmetalloproteinase inhibitor is an inhibitor of gelatinase.
 8. The methodof claim 6 wherein the matrix metalloproteinase inhibitor inhibits atleast one of MMP-2 and MMP-9.
 9. The method of claim 6 wherein thematrix metalloproteinase inhibitor is a hydroxamate compound.
 10. Themethod of claim 6 wherein the matrix metalloproteinase inhibitor isselected from the group consisting of marimastat, batimastat, AG-3340,doxycycline and pharmaceutically acceptable salts thereof.
 11. Themethod of claim 6 wherein the combination is administered in asequential manner.
 12. The method of claim 6 wherein the combination isadministered in a substantially simultaneous manner.
 13. The method ofclaim 6 wherein the neoplasia disorder is a cancer selected from thegroup consisting of colorectal cancer, breast cancer, prostate cancer,bladder cancer, ovary cancer, cervical cancer, gastrointestinal cancer,head and neck cancer, and lung cancer.
 14. The method of claim 6,further comprising administering to the mammal a therapeuticallyeffective amount of radiation therapy.